Tricyclic androgen receptor modulator compounds and methods

ABSTRACT

This invention relates to non-steroidal tricyclic compounds that are modulators of androgen receptors and to methods for making and using such compounds.

RELATED APPLICATION

The present application claims the benefit of priority to U.S.Provisional Application No. 60/271,189, filed on Feb. 23, 2001 which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to non-steroidal compounds that are modulators(i.e. agonists, partial agonists and antagonists) of androgen receptorsand to methods for making and using such compounds.

BACKGROUND OF THE INVENTION

Intracellular receptors (IRs) form a class of structurally-relatedgenetic regulators scientists have named “ligand dependent transcriptionfactors” (R. M. Evans, Science, 240:889, 1988). Sex steroid hormonereceptors are a recognized subset of the IRs, including androgenreceptor (AR), progesterone receptor (PR) and estrogen receptor (ER).Regulation of a gene by such factors requires both the receptor itselfand a corresponding ligand, which has the ability to selectively bind tothe receptor in a way that affects gene transcription.

The natural hormones for sex steroid receptors have been known for along time, such as testosterone for AR and progesterone for PR. Acompound that binds to a receptor and mimics the effect of the nativehormone is referred to as an “agonist”, while a compound that inhibitsthe effect of the native hormone is called an “antagonist.” The term“modulators” refers to compounds that are agonists, partial agonists orantagonists.

Synthetic female sex hormones have been widely used in oralcontraception, hormone replacement therapy and the treatment ofhormone-dependent disorders. The development of new generations ofselective estrogen receptor modulators (SERMs) significantly improvedwomen's health. On the other hand, similar hormone therapy for men hasnot been fully explored due to lack of availability of selective, orallyadministered, safe agents.

A group of hydroquinoline derivatives was recently described as ARmodulators (e.g., U.S. Pat. No. 5,696,130). This group of AR modulatorswas developed by using cell-based high-throughput assays, termedcotransfection assays.

The entire disclosures of the publications and references referred toherein are incorporated by reference herein and are not admitted to beprior art.

SUMMARY OF THE INVENTION

The present invention is directed to tricyclic androgen receptormodulator compounds. This invention is also directed to pharmaceuticalcompositions containing such compounds as well as methods of using suchcompounds and pharmaceutical compositions for modulating processesmediated by androgen receptor (AR). More particularly, the inventionrelates to nonsteroidal compounds and compositions that may be highaffinity, high specificity agonists, partial agonists (i.e., partialactivators and/or tissue-specific activators) or antagonists forandrogen receptor. Also provided are methods of making such compoundsand pharmaceutical compositions, as well as intermediates used in theirsynthesis.

The present invention provides a novel class of AR modulator compoundsof the formula:

wherein:

R¹ is selected from the group of hydrogen, F, Cl, Br, I, NO₂, OR², SR¹²,SOR¹², SO₂R¹², NR¹²R¹³, C₁–C₈ alkyl, C₁–C₈ haloalkyl and C₁–C₈heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may beoptionally substituted;

R² is selected from the group of hydrogen, F, Cl, Br, I, CH₃, CF₃, CHF₂,CH₂F, CF₂Cl, CN, CF₂OR¹², CH₂OR¹², OR¹², SR¹², SOR¹², SO₂R¹², NR¹²R¹³,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkenyl and C₂–C₈alkynyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl and alkynylgroups may be optionally substituted;

R³ through R⁸ each independently is selected from the group of hydrogen,F, Cl, Br, I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl,heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl,alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups may beoptionally substituted; or

R³ and R⁵ taken together form a bond; or

R⁵ and R⁷ taken together form a bond; or

R⁴ and R⁶ taken together form a three- to eight-membered saturated orunsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic orheterocyclic ring may optionally substituted; or

R⁶ and R⁸ taken together form a three- to eight-membered saturated orunsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic orheterocyclic ring may optionally substituted;

R⁹ and R¹⁰ each independently is selected from the group of hydrogen, F,Cl, Br, I, CN, OR¹², NR¹²R¹³, C_(m)(R¹²)_(2m)OR¹³, SR¹², SOR¹², SO₂R¹²,NR¹²C(O)R¹³, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl and arylalkylgroups may be optionally substituted;

R¹¹ is selected from the group of hydrogen, F, Br, Cl, I, CN, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, OR¹⁴, NR¹⁴R¹³, SR¹⁴, CH₂R¹⁴,C(O)R¹⁴, CO₂R¹⁴, C(O)NR¹⁴R¹³, SOR¹⁴ and SO₂R¹⁴, wherein the alkyl,haloalkyl and heteroalkyl groups may be optionally substituted;

R¹² and R¹³ each independently is selected from the group of hydrogen,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkenyl, C₂–C₈alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,alkenyl, alkynyl, heteroaryl and aryl groups may be optionallysubstituted;

R¹⁴ is selected from the group of hydrogen, C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, aryl, heteroaryl, C(O)R¹⁵, CO₂R¹⁵ andC(O)NR¹⁵R¹⁶, wherein the alkyl, haloalkyl, heteroalkyl, aryl andheteroaryl groups may be optionally substituted;

R¹⁵ and R¹⁶ each independently is selected from the group of hydrogen,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, wherein the alkyl,haloalkyl and heteroalkyl groups may be optionally substituted;

W is O or S;

X is selected from the group of O, S and N{R¹⁴};

Y is selected from the group of O, S, N{R¹²}, N{OR¹²} and CR¹²R¹³;

Z is selected from the group of O, S and N{R¹²};

n is 0, 1 or 2;

m is 0, 1, or 2;

and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkyl,” alone or in combination, refers to an optionallysubstituted straight-chain or branched-chain alkyl radical having from 1to about 12 carbon atoms. The term also includes substitutedstraight-chain or branched-chain alkyl radicals having from 1 to about 6carbon atoms as well as those having from 1 to about 4 carbon atoms.Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl,heptyl, octyl and the like.

The term “alkenyl,” alone or in combination, refers to an optionallysubstituted straight-chain or branched-chain hydrocarbon radical havingone or more carbon-carbon double-bonds and having from 2 to about 18carbon atoms. The term also includes substituted straight-chain orbranched-chain hydrocarbon radicals having one or more carbon-carbondouble bonds and having from 2 to about 6 carbon atoms as well as thosehaving from 2 to about 4 carbon atoms. Examples of alkenyl radicalsinclude ethenyl, propenyl, butenyl, 1,4-butadienyl and the like.

The term “alkynyl,” alone or in combination, refers to an optionallysubstituted straight-chain or branched-chain hydrocarbon radical havingone or more carbon-carbon triple-bonds and having from 2 to about 12carbon atoms. The term also includes substituted straight-chain orbranched-chain hydrocarbon radicals having one or more carbon-carbontriple bonds and having from 2 to about 6 carbon atoms as well as thosehaving from 2 to about 4 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl, butynyl and the like.

The term “heteroalkyl” refers to alkyl groups, as described above, inwhich one or more skeletal atoms are oxygen, nitrogen, sulfur orcombinations thereof. The term heteroalkyl also includes alkyl groups inwhich one 1 to about 6 skeletal atoms are oxygen, nitrogen, sulfur orcombinations thereof, as well as those in which 1 to 4 skeletal atomsare oxygen, nitrogen, sulfur or combinations thereof and those in which1 to 2 skeletal atoms are oxygen, nitrogen, sulfur or combinationsthereof.

The term “alkoxy,” alone or in combination, refers to an alkyl etherradical, alkyl-O—, wherein the term alkyl is defined as above. Examplesof alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “aryloxy,” alone or in combination, refers to an aryl etherradical wherein the term aryl is defined as below. Examples of aryloxyradicals include phenoxy, benzyloxy and the like.

The term “alkylthio,” alone or in combination, refers to an alkyl thioradical, alkyl-S—, wherein the term alkyl is defined as above.

The term “arylthio,” alone or in combination, refers to an aryl thioradical, aryl-S—, wherein the term aryl is defined as below.

The term “oxo” refers to ═O.

The term “aryl,” alone or in combination, refers to an optionallysubstituted aromatic ring system. The term aryl includes monocyclicaromatic rings, polyaromatic rings and polycyclic aromatic ring systemscontaining from six to about twenty carbon atoms. The term aryl alsoincludes monocyclic aromatic rings, polyaromatic rings and polycyclicring systems containing from 6 to about 12 carbon atoms, as well asthose containing from 6 to about 10 carbon atoms. The polyaromatic andpolycyclic aromatic rings systems may contain from two to four rings.Examples of aryl groups include, without limitation, phenyl, biphenyl,naphthyl and anthryl ring systems.

The term “heteroaryl” refers to optionally substituted aromatic ringsystems containing from about five to about 20 skeletal ring atoms andhaving one or more heteroatoms such as, for example, oxygen, nitrogenand sulfur. The term heteroaryl also includes optionally substitutedaromatic ring systems having from 5 to about 12 skeletal ring atoms, aswell as those having from 5 to about 10 skeletal ring atoms. The termheteroaryl may include five- or six-membered heterocyclic rings,polycyclic heteroaromatic ring systems and polyheteroaromatic ringsystems where the ring system has two, three or four rings. The termsheterocyclic, polycyclic heteroaromatic and polyheteroaromatic includering systems containing optionally substituted heteroaromatic ringshaving more than one heteroatom as described above (e.g., a six memberedring with two nitrogens), including polyheterocyclic ring systems offrom two to four rings. The term heteroaryl includes ring systems suchas, for example, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl,indolyl, quinolinyl, N-alkyl pyrrolyl, pyridyl-N-oxide, pyrimidoyl,pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, benzothiophenyl, purinyl,indolizinyl, thienyl and the like.

The term “heteroarylalkyl” refers to a C₁–C₄ alkyl group containing aheteroaryl group, each of which may be optionally substituted.

The term “heteroarylthio” refers to the group —S-heteroaryl.

The term “acyloxy” refers to the ester group —OC(O)—R, where R ishydrogen, alkyl, alkenyl, alkynyl, aryl, or arylalkyl, wherein thealkyl, alkenyl, alkynyl and arylalkyl groups may be optionallysubstituted.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl orarylalkyl, wherein the alkyl, aryl and arylalkyl groups may beoptionally substituted.

The term “carboxamido” refers to

where R and R′ each independently is selected from the group ofhydrogen, alkyl, aryl and arylalkyl, wherein the alkyl, aryl andarylalkyl groups may be optionally substituted.

The term “cycloalkyl”, alone or in combination, refers to a monocyclic,bicyclic or tricyclic alkyl radical wherein each cyclic moiety has from3 to about 8 carbon atoms. Examples of cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “arylalkyl,” alone or in combination, refers to an alkylradical as defined above in which one hydrogen atom is replaced by anaryl radical as defined above, such as, for example, benzyl,2-phenylethyl and the like.

The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy includealkyl, alkenyl, alkynyl and alkoxy structures, as described above, thatare substituted with one or more fluorines, chlorines, bromines oriodines, or with combinations thereof.

The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl,alkenyl, haloalkyl and heteroalkyl include optionally substitutedcycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl,haloalkyl and heteroalkyl groups.

The term “carbocycle” includes optionally substituted, saturated orunsaturated, three- to eight-membered cyclic structures in which all ofthe skeletal atoms are carbon.

The term “heterocycle” includes optionally substituted, saturated orunsaturated, three- to eight-membered cyclic structures in which one ormore skeletal atoms is oxygen, nitrogen, sulfur, or combinationsthereof.

The term “acyl” includes alkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl substituents attached to a compound via a carbonylfunctionality (e.g., —CO-alkyl, —CO-aryl, —CO-arylalkyl or—CO-heteroarylalkyl, etc.).

“Optionally substituted” groups may be substituted or unsubstituted. Thesubstituents of an “optionally substituted” group may include, withoutlimitation, one or more substituents independently selected from thefollowing groups or designated subsets thereof: alkyl, alkenyl, alkynyl,heteroalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, aryloxy, haloalkoxy,amino, alkylamino, dialkylamino, alkylthio, arylthio, heteroarylthio,oxo, carboxyesters, carboxamido, acyloxy, hydrogen, F, Cl, Br, I, CN,NO₂, NH₂, N₃, NHCH₃, N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CH₃, CF₃,C(O)CH₃, CO₂CH₃, CO₂H, C(O)NH₂, OR⁹, SR⁹ and NR¹⁰R¹¹. An optionallysubstituted group may be unsubstituted (e.g., —CH₂CH₃), fullysubstituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstututed (e.g., —CH₂CF₃).

The term “halogen” includes F, Cl, Br and I.

The term “mediate” means affect or influence. Thus, for example,conditions mediated by an androgen receptor are those in which anandrogen receptor plays a role. Androgen receptors are known to play arole in conditions including, for example, acne, male-pattern baldness,sexual dysfunction, impotence, wasting diseases, hirsutism,hypogonadism, prostatic hyperplasia, osteoporosis, cancer cachexia, andhormone-dependent cancers.

The term “selective” refers to compounds that display reactivity towardsa particular receptor (e.g., an androgen receptor) without displayingsubstantial cross-reactivity towards another receptor (e.g.,glucocorticoid receptor). Thus, for example, selective compounds of thepresent invention may display reactivity towards androgen receptorswithout displaying substantial cross-reactivity towards glucocorticoidreceptors.

In one embodiment, selective compounds of the present invention displayat least 50-fold greater reactivity towards a particular receptor thantowards another receptor. In another embodiment, selective compounds ofthe present invention display at least 100-fold greater reactivitytowards a particular receptor than towards another receptor. In yetanother embodiment, selective compounds of the present invention displayat least 500-fold greater reactivity towards a particular receptor thantowards another receptor. In still another embodiment, selectivecompounds of the present invention display at least 1,000-fold greaterreactivity towards a particular receptor than towards another receptor.

Compounds of the present invention may be represented by the formulae:

wherein:

R¹ is selected from the group of hydrogen, F, Cl, Br, I, NO₂, OR¹²,SR¹², SOR¹², SO₂R¹², NR¹²R¹³, C₁–C₈ alkyl, C₁–C₈ haloalkyl and C₁–C₈heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups may beoptionally substituted;

R² is selected from the group of hydrogen, F, Cl, Br, I, CH₃, CF₃, CHF₂,CH₂F, CF₂Cl, CN, CF₂OR¹², CH₂OR¹², OR¹², SR¹², SOR¹², SO₂R¹², NR¹²R¹³,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkenyl and C₂–C₈alkynyl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl and alkynylgroups may be optionally substituted;

R³ through R⁸ each independently is selected from the group of hydrogen,F, Cl, Br, I, OR¹², NR¹²R¹³, SR¹², SO₂R¹², SOR¹², C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl,heteroaryl and arylalkyl, wherein the alkyl, haloalkyl, heteroalkyl,alkynyl, alkenyl, aryl, heteroaryl and arylalkyl groups may beoptionally substituted; or

R³ and R⁵ taken together form a bond; or

R⁵ and R⁷ taken together form a bond; or

R⁴ and R⁶ taken together form a three- to eight-membered saturated orunsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic orheterocyclic ring may optionally substituted; or

R⁶ and R⁸ taken together form a three- to eight-membered saturated orunsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic orheterocyclic ring may optionally substituted;

R⁹ and R¹⁰ each independently is selected from the group of hydrogen, F,Cl, Br, I, CN, OR¹², NR¹²R¹³, C_(m)(R¹²)_(2m)OR¹³, SR¹², SOR¹², SO₂R¹²,NR¹²C(O)R¹³, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl and arylalkylgroups may be optionally substituted;

R¹¹ is selected from the group of hydrogen, F, Br, Cl, I, CN, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, OR¹⁴, NR¹⁴R¹³, SR¹⁴, CH₂R¹⁴,C(O)R¹⁴, CO₂R¹⁴, C(O)NR¹⁴R¹³, SOR¹⁴ and SO₂R¹⁴, wherein the alkyl,haloalkyl and heteroalkyl groups may be optionally substituted;

R¹² and R¹³ each independently is selected from the group of hydrogen,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkenyl, C₂–C₈alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,alkenyl, alkynyl, heteroaryl and aryl groups may be optionallysubstituted;

R¹⁴ is selected from the group of hydrogen, C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, aryl, heteroaryl, C(O)R¹⁵, CO₂R¹⁵ andC(O)NR¹⁵R¹⁶, wherein the alkyl, haloalkyl, heteroalkyl, aryl andheteroaryl groups may be optionally substituted;

R¹⁵ and R¹⁶ each independently is selected from the group of hydrogen,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, wherein the alkyl,haloalkyl and heteroalkyl groups may be optionally substituted;

W is O or S;

X is selected from the group of O, S and N{R¹⁴};

Y is selected from the group of O, S, N{R¹²}, N{OR¹²} and CR¹²R¹³;

Z is selected from the group of O, S and N{R¹²};

n is 0, 1 or 2;

m is 0, 1, or 2;

and pharmaceutically acceptable salts thereof.

In one aspect, the present the invention provides compounds representedby formula I through VIII. In another aspect, the present inventionprovides a pharmaceutical composition comprising an effective amount ofan AR modulating compound of formula I through VIII shown above, whereinR¹ through R¹⁶, m, n, W, X, Y, and Z are as described above.

In another aspect, the present invention provides a method of modulatingprocesses mediated by ARs by administering to a patient apharmaceutically effective amount of a compound of formula I throughVIII shown above, wherein R¹ through R¹⁶, m, n, W, X, Y, and Z are asdescribed above. In one aspect, the modulation is activation, while inanother aspect, the modulation is inhibition. In each case, the methodinvolves administering to a patient a pharmaceutically effective amountof a compound of formula I through VIII shown above, wherein R¹ throughR¹⁶, m, n, W, X, Y, and Z are as described above.

With regard to the foregoing variables, the inventors contemplate anycombination of the Markush groups as set forth above and as described inthe following table.

TABLE A Table of Markush Groups by Variable Markush Group Markush GroupMarkush Group Markush Group A B C D R¹ hydrogen, F, Cl, hydrogen, F, Cl,hydrogen, F and hydrogen and F Br, I, C₁–C₆ alkyl, C₁–C₄ alkyl, C₁–C₄optionally C₁–C₆ haloalkyl haloalkyl and substituted C₁–C₂ and C₁–C₆C₁–C₄ heteroalkyl, alkyl heteroalkyl, wherein the alkyl, wherein thealkyl, haloalkyl and haloalkyl and heteroalkyl groups heteroalkyl groupsmay be optionally may be optionally substituted substituted R² hydrogen,F, Cl, hydrogen, F, Cl, hydrogen, F, Cl, hydrogen, F, Cl, Br, CF₃,CF₂Cl, Br, CF₃, CF₂Cl, C₁–C₄ alkyl, C₁–C₄ CF₃, CF₂Cl, CF₂H, CFH₂, CF₂H,CFH₂, haloalkyl and CF₂H, CFH₂ and C₁–C₆ alkyl, C₁–C₆ C₁–C₄ alkyl, C₁–C₄C₁–C₄ heteroalkyl, optionally haloalkyl and haloalkyl, C₁–C₄ wherein thealkyl, substituted C₁–C₄ C₁–C₆ heteroalkyl, heteroalkyl, C₂–C₄ haloalkyland alkyl wherein the alkyl, alkenyl and C₂–C₄ heteroalkyl groupshaloalkyl and alkynyl, wherein may be optionally heteroalkyl groups thealkyl, substituted may be optionally haloalkyl, substituted heteroalkyl,CF₂OR¹², alkenyl and CH₂OR¹², OR¹², alkynyl groups SR¹², SOR¹², may beoptionally SO₂R¹² and substituted NR¹²R¹³ R³ hydrogen, C₁–C₆ hydrogen,C₁–C₄ hydrogen and hydrogen alkyl, C₁–C₆ alkyl, C₁–C₄ optionallyhaloalkyl and haloalkyl and substituted C₁–C₄ C₁–C₆ heteroalkyl, C₁–C₄heteroalkyl, alkyl wherein the alkyl, wherein the alkyl, haloalkyl andhaloalkyl and heteroalkyl groups heteroalkyl groups may be optionallymay be optionally substituted substituted R³ and R⁵ taken together forma bond R⁴ hydrogen, C₁–C₆ hydrogen, C₁–C₆ hydrogen, C₁–C₄ hydrogen andalkyl, C₁–C₆ alkyl, C₁–C₆ alkyl, C₁–C₄ C₁–C₄ alkyl haloalkyl andhaloalkyl and haloalkyl and C₁–C₆ heteroalkyl, C₁–C₆ heteroalkyl, C₁–C₄heteroalkyl, wherein the alkyl, wherein the alkyl, wherein the alkyl,haloalkyl and haloalkyl and haloalkyl and heteroalkyl groups heteroalkylgroups heteroalkyl groups may be optionally may be optionally may beoptionally substituted substituted substituted R⁴ and R⁶ taken togetherform a four to six membered saturated or unsaturated carbocyclic orheterocyclic ring, wherein the carbocyclic or heterocyclic ring may beoptionally substituted R⁵ hydrogen, C₁–C₆ hydrogen, C₁–C₄ hydrogen,C₁–C₄ hydrogen and alkyl, C₁–C₆ alkyl, C₁–C₄ alkyl, C₁–C₄ C₁–C₄ alkylhaloalkyl and haloalkyl and haloalkyl and C₁–C₆ heteroalkyl, C₁–C₄heteroalkyl, C₁–C₄ heteroalkyl, wherein the alkyl, wherein the alkyl,wherein the alkyl, haloalkyl and haloalkyl and haloalkyl and heteroalkylgroups heteroalkyl groups heteroalkyl groups may be optionally may beoptionally may be optionally substituted substituted substituted R⁵ andR⁷ taken R⁵ and R⁷ taken together form a together form a bond bond R³and R⁵ taken together form a bond R⁶ hydrogen, C₁–C₆ hydrogen, C₁–C₄hydrogen, C₁–C₆ hydrogen, C₁–C₄ alkyl, C₁–C₆ halo- alkyl, C₁–C₄ halo-alkyl, C₁–C₆ halo- alkyl, C₁–C₄ halo- alkyl, C₁–C₆ alkyl, C₁–C₄ alkyland C₁–C₆ alkyl and C₁–C₄ heteroalkyl, heteroalkyl, heteroalkyl,heteroalkyl, heteroaryl and heteroaryl and wherein the alkyl, whereinthe alkyl, aryl, wherein the aryl, wherein the haloalkyl and haloalkyland alkyl, haloalkyl, alkyl, haloalkyl, heteroalkyl groups heteroalkylgroups heteroalkyl, heteroalkyl, may be optionally may be optionallyheteroaryl and heteroaryl and substituted substituted aryl groups mayaryl groups may be optionally be optionally substituted substituted R⁴and R⁶ taken R⁶ and R⁸ taken R⁶ and R⁸ taken together form a togetherform a together form a four to six mem- four to six four to six beredsaturated or membered membered unsaturated saturated or saturated orcarbocyclic or unsaturated unsaturated heterocyclic ring, carbocyclic orcarbocyclic or wherein the heterocyclic ring, heterocyclic ring,carbocyclic or wherein the wherein the heterocyclic ring carbocyclic orcarbocyclic or may be optionally heterocyclic ring heterocyclic ringsubstituted may optionally may optionally substituted substituted R⁶ andR⁸ taken together form a three to eight membered saturated orunsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic orheterocyclic ring may optionally substituted R⁷ hydrogen, C₁–C₆hydrogen, C₁–C₄ hydrogen, C₁–C₄ hydrogen and alkyl, C₁–C₆ alkyl, C₁–C₄alkyl, C₁–C₄ C₁–C₄ alkyl haloalkyl and haloalkyl and haloalkyl and C₁–C₆heteroalkyl, C₁–C₄ heteroalkyl, C₁–C₄ heteroalkyl, wherein the alkyl,wherein the alkyl, wherein the alkyl, haloalkyl and haloalkyl andhaloalkyl and heteroalkyl groups heteroalkyl groups heteroalkyl groupsmay be optionally may be optionally may be optionally substitutedsubstituted substituted R⁵ and R⁷ taken R⁵ and R⁷ taken together form atogether form a bond bond R⁸ hydrogen, C₁–C₆ hydrogen, C₁–C₄ hydrogen,C₁–C₆ hydrogen, methyl, alkyl, C₁–C₆ halo- alkyl, C₁–C₄ alkyl, C₁–C₆ andethyl alkyl, C₁–C₆ haloalkyl, C₁–C₄ haloalkyl and heteroalkyl,heteroalkyl, C₁–C₆ heteroalkyl, heteroaryl and heteroaryl and whereinthe alkyl, aryl, wherein the aryl, wherein the haloalkyl, alkyl,haloalkyl, alkyl, haloalkyl, heteroalkyl groups heteroalkyl,heteroalkyl, may be optionally heteroaryl and heteroaryl and substitutedaryl groups may aryl groups may be optionally be optionally substitutedsubstituted R⁶ and R⁸ taken R⁶ and R⁸ taken R⁶ and R⁸ taken R⁶ and R⁸taken together form a together form a together form a together form athree- to eight- four- to six- four- to six- four- to six- memberedmembered membered membered saturated or saturated or saturated orcarbocyclic or unsaturated unsaturated unsaturated heterocyclic ring,carbocyclic or carbocyclic or carbocyclic or wherein the heterocyclicring, heterocyclic ring, heterocyclic ring, carbocyclic or wherein thewherein the wherein the heterocyclic ring carbocyclic or carbocyclic orcarbocyclic or may optionally heterocyclic ring heterocyclic ringheterocyclic ring substituted may be optionally may optionally mayoptionally substituted substituted substituted R⁹ hydrogen, F, Cl,hydrogen, F, Cl, hydrogen, F and hydrogen Br, C₁–C₆ alkyl, C₁–C₄ alkyl,C₁–C₄ CH₃ C₁–C₆ haloalkyl haloalkyl and and C₁–C₆ C₁–C₄ heteroalkyl,heteroalkyl, wherein the alkyl, wherein the alkyl, haloalkyl andhaloalkyl and heteroalkyl groups heteroalkyl groups may be optionallymay be optionally substituted substituted R¹⁰ hydrogen, F, Cl, hydrogen,F, Cl, hydrogen, F and hydrogen Br, C₁–C₆ alkyl, C₁–C₄ alkyl, C₁–C₄ CH₃C₁–C₆ haloalkyl haloalkyl and and C₁–C₆ C₁–C₄ heteroalkyl, heteroalkyl,wherein the alkyl, wherein the alkyl, haloalkyl and haloalkyl andheteroalkyl groups heteroalkyl groups may be optionally may beoptionally substituted substituted R¹¹ hydrogen, F, Br, hydrogen, F, Cl,hydrogen, F, Cl, OR¹⁴ Cl, CN, C₁–C₆ OR¹⁴, SR¹⁴, OR¹⁴ and SR¹⁴ alkyl,C₁–C₆ NR¹⁴R¹³, CH₂R¹⁴, haloalkyl, C₁–C₆ C(O)R¹⁴, CO₂R¹⁴, heteroalkyl,OR¹⁴, C(O)NR¹⁴R¹³, NR¹⁴R¹³, SR¹⁴, SOR¹⁴, SO₂R¹⁴ CH₂R¹⁴, C(O)R¹⁴, andoptionally CO₂R¹⁴, substituted C₁–C₄ C(O)NR¹⁴R¹³, alkyl SOR¹⁴ andSO₂R¹⁴, wherein the alkyl, haloalkyl and heteroalkyl groups may beoptionally substituted R¹² hydrogen, C₁–C₆ hydrogen, C₁–C₆ hydrogen,C₁–C₄ hydrogen and alkyl, C₁–C₆ alkyl, C₁–C₆ alkyl, C₁–C₄ C₁–C₄ alkylhaloalkyl, C₁–C₆ haloalkyl, C₁–C₆ haloalkyl and C₁– heteroalkyl, C₂–C₆heteroalkyl, C₂–C₆ C₄ heteroalkyl, alkenyl, C₂–C₆ alkenyl and C₂–C₆wherein the alkyl, alkynyl, alkynyl, wherein haloalkyl and heteroaryland the alkyl, heteroalkyl groups aryl, wherein the haloalkyl, may beoptionally alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,alkenyl, and alkenyl, alkynyl, alkynyl groups heteroaryl and may beoptionally aryl groups may substituted be optionally substituted R¹³hydrogen, C₁–C₆ hydrogen, C₁–C₆ hydrogen, C₁–C₄ hydrogen and alkyl,C₁–C₆ alkyl, C₁–C₆ alkyl, C₁–C₄ C₁–C₄ alkyl haloalkyl, C₁–C₆ haloalkyl,C₁–C₆ haloalkyl and C1– heteroalkyl, C₂–C₆ heteroalkyl, C₂–C₆ C₄heteroalkyl, alkenyl, C₂–C₆ alkenyl and C₂–C₆ wherein the alkyl,alkynyl, alkynyl, wherein haloalkyl and heteroaryl and the alkyl,heteroalkyl groups aryl, wherein the haloalkyl, may be optionally alkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, alkenyl, and alkenyl,alkynyl, alkynyl groups heteroaryl and may be optionally aryl groups maysubstituted be optionally substituted R¹⁴ hydrogen, C₁–C₆ hydrogen,hydrogen, hydrogen and alkyl, C₁–C₆ C(O)R¹⁵, optionally C₁–C₂ alkylhaloalkyl, C₁–C₆ C(O)NR¹⁵R¹⁶, C₁– substituted C₁–C₂ heteroalkyl, aryl,C₄ alkyl, C₁–C₄ alkyl, C(O)CH₃ heteroaryl, haloalkyl, and C₁– andC(O)N(CH₃)₂ C(O)R¹⁵, CO₂R¹⁵ C₄ heteroalkyl, and C(O)NR¹⁵R¹⁶, wherein thealkyl, wherein the alkyl, haloalkyl and haloalkyl, heteroalkyl groupsheteroalkyl, aryl may be optionally and heteroaryl substituted groupsmay be optionally substituted R¹⁵ hydrogen, C₁–C₆ hydrogen, C₁–C₄hydrogen, C₁–C₂ hydrogen and alkyl, C₁–C₆ alkyl, C₁–C₄ alkyl, C₁–C₂C₁–C₂ alkyl haloalkyl, and haloalkyl, and haloalkyl, and C₁–C₆heteroalkyl, C₁–C₄ heteroalkyl, C₁–C₂ heteroalkyl, wherein the alkyl,wherein the alkyl, wherein the alkyl, haloalkyl and haloalkyl andhaloalkyl and heteroalkyl groups heteroalkyl groups heteroalkyl groupsmay be optionally may be optionally may be optionally substitutedsubstituted substituted R¹⁶ hydrogen, C₁–C₆ hydrogen, C₁–C₄ hydrogen,C₁–C₂ hydrogen and alkyl, C₁–C₆ alkyl, C₁–C₄ alkyl, C₁–C₂ C₁–C₂ alkylhaloalkyl and haloalkyl and haloalkyl and C₁–C₆ heteroalkyl, C₁–C₄heteroalkyl, C₁–C₂ heteroalkyl, wherein the alkyl, wherein the alkyl,wherein the alkyl, haloalkyl and haloalkyl and haloalkyl and heteroalkylgroups heteroalkyl groups heteroalkyl groups may be optionally may beoptionally may be optionally substituted substituted substituted W O andS O S X O and N{R¹⁴} N{R¹⁴} O NH Y O and S O S Z O and N{R¹²} N{R¹²} O n0 and 1 0 1 m 0 and 1 0 1

The compounds of the present invention may be synthesized aspharmaceutically acceptable salts for incorporation into variouspharmaceutical compositions. As used herein, pharmaceutically acceptablesalts include, but are not limited to, hydrochloric, hydrobromic,hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic,nicotinic, succinic, oxalic, phosphoric, malonic, salicylic,phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine,nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc,lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric,triethylamino, dimethylamino and tris(hydroxymethyl)aminomethane and thelike and suitable combination of any two or more thereof. Additionalpharmaceutically acceptable salts are known to those skilled in the art.

AR agonist, partial agonist and antagonist compounds of the presentinvention may be useful in the treatment of conditions including, butnot limited to, hypogonadism, frailty, wasting diseases, cachexia,osteoporosis, hirsutism, acne, male-pattern baldness, prostatichyperplasia, various hormone-dependent disorders and cancers, including,without limitation, prostate and breast cancer. The compounds of thepresent invention may also prove useful in male hormone replacementtherapy, female androgen replacement therapy, stimulation ofhematopoiesis, and as anabolic agents and libido stimulants.

It is understood by those skilled in the art that although the compoundsof the present invention may be typically employed as selectiveagonists, partial agonists or antagonists, there may be instances wherea compound with a mixed steroid receptor profile is desirable.

Furthermore, it is understood by those skilled in the art that thecompounds of the present invention, as well as pharmaceuticalcompositions and formulations containing these compounds, can be used ina wide variety of combination therapies to treat the conditions anddiseases described above. Thus, the compounds of the present inventioncan be used in combination with other hormones and other therapies,including, without limitation, chemotherapeutic agents such ascytostatic and cytotoxic agents, immunological modifiers such asinterferons, interleukins, growth hormones and other cytokines, hormonetherapies, surgery and radiation therapy.

Representative AR modulator compounds (i.e., agonists, partial agonistsand antagonists) according to the present invention include:

-   5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 104);-   5,6,7,8-Tetrahydro-7,7-diethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 105);-   7,8-Dihydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 106);-   5,6,7,8-Tetrahydro-7,7,8-trimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 107);-   8-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 108);-   5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 109);-   8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethyl-pyridino[3,2-f]quinolin-2(1H)-one    (Compound 110);-   6-Hydrazino-4-trifluoromethylquinolin-2(1H)-one (Compound 111);-   6-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 112);-   5-Isopropyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 113);-   5-Allyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 114);-   5-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 115);-   5-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 116);-   4-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 117);-   4-Trifluoromethyl-5,6,7,8,9,10-hexahydrocycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 118);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 119);-   (±)-6,6a,7,8,9,9a(cis)-Hexahydro-6-trifluoroethyl-4-trifluoromethylcyclopentano-[i]pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 120);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 121);-   (±)-6,6a,7,8,9,9a(cis)-Hexahydro-6-ethyl-4-trifluoromethylcyclopentano-[i]pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 122);-   (±)-5,6-Dihydro-5,6-cis-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 123);-   (±)-7,8-Dihydro-7,8-cis-dimethyl-6-trifluoroethyl-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 124);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one    (Compound 125);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-furanylmethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 126);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 127);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 128);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 129);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 130);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2-dimethoxyethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 131);-   (±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 132);-   (±)-4c,5,6,7,8,9,9a(cis),10-Octahydro-10-(2,2,2-trifluoroethyl)-4-trifluoromethyl-cycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 133);-   (±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 134);-   (±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 135);-   (±)-5,6-cis-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 136);-   (±)-5,6-cis-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 137);-   (±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 138);-   (±)-5,6-cis-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 139);-   (±)-5,6-cis-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 140);-   (±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 141);-   (±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 142);-   (±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 143);-   (±)-5,6-cis-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 144);-   (±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 145);-   (±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 146);-   (±)-5,6-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 147);-   6-Ethyl-5-methyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one (Compound 148);-   (±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 149);-   5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 150);-   6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 151);-   6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 152);-   6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 153);-   5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 154);-   5-Ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 155);-   5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 156);-   8-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 157);-   9-Trifluoroethyl-4-trifluoromethyl-9H-benzo[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 158);-   6-Trifluoroethyl-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[i]pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 159);-   5-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 160);-   5-(4-Fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 161);-   5-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 162);-   7-Ethyl-8-methyl-6-(2,2,2-trifluoroethyl)-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 163);-   5-Hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 164);-   5-Methyl-6-(1-hydroxyethyl)-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 165);-   5-Methyl-6-acetyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 166);-   5-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 167);-   5-Acetyloxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 168);-   2-Acetyloxy-5-hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinoline    (Compound 169);-   6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 170);-   5-Ethoxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 171);-   6-(1-Methoxyethyl)-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 172);-   7-Allyl-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one    (Compound 173);-   6-Ethyl-7-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one    (Compound 175);-   7-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one    (Compound 176);-   7-(2-Hydroxyethyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one    (Compound 177);-   (+)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 178);-   (−)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 179);-   4-Trifluoromethyl-6,7-dihydro-7,7,9-trimethyl-pyrido[2,3-g]quinolin-2(1H)-one    (Compound 180);-   8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-5,7,7-trimethylpyrido[3,2-f]quinolin-2(1H)-one    (Compound 182);-   4,5,7-Tri(trifluoromethyl)pyrido[3,2-f]quinolin-2(1H)-one (Compound    185);-   5,7-Bis(trifluoromethyl)pyrido[3,2-f]quinolin-2(1H)-one (Compound    186);-   4-Trifluoromethyl-7-methyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 187);-   4-Trifluoromethyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 190);-   4-Trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 192);-   4-Trifluoromethyl-7-methyl-6-propyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 194);-   4-Trifluoromethyl-7-methyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 195);-   4-Trifluoromethyl-7-methyl-6-ethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 196);-   4-Trifluoromethyl-7-methyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 197);-   4-Trifluoromethyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 198);-   4-Trifluoromethyl-6-propyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 199);-   4-Trifluoromethyl-6-ethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 200);-   4-Trifluoromethyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 201);-   6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 202);-   6,7-Dihydro-8,8,10-trimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 206);-   (±)-6,7-Dihydro-6-ethyl-4-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 210);-   (±)-7,8-Dihydro-8-ethyl-4-methyl-6H-pyrano[2,3-f]quinolin-2(1H)-one    (Compound 215);-   (±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 216);-   (−)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 217);-   (+)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 218);-   (±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 219);-   (±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-1-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 220);-   (±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-1-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 221);-   (±)-6,7-Dihydro-6-ethyl-2,4-bis(trifluoromethyl)-8H-pyrano[3,2-g]quinoline    (Compound 222);-   6,8,8-Trimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin (Compound    223);-   6-Ethyl-8,8-dimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin    (Compound 227);-   (±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 228);-   (±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 229);-   7,8-Dihydro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 230);-   6-(2,2,2-Trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 231);-   8-Chloro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 232);-   5-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 233);-   6-Formyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 234);-   5,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 235).

Within such group, representative compounds include:

-   8-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 108);-   5,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3,2-f]quinolin-2(1H)-one    (Compound 109);-   8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethyl-pyridino[3,2-f]quinolin-2(1H)-one    (Compound 110);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 119);-   (±)-6,6a,7,8,9,9a(cis)-Hexahydro-6-trifluoroethyl-4-trifluoromethylcyclopentano-[i]pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 120);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 121);-   (±)-5,6-Dihydro-5,6-cis-dimethyl-7-trifluoroethyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 123);-   (±)-7,8-Dihydro-7,8-cis-dimethyl-6-trifluoroethyl-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 124);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one    (Compound 125);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 129);-   (±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 130);-   (±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 132);-   (±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 134);-   (±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 135);-   (±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 145);-   (±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 146);-   (±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 149);-   5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 150);-   6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 152);-   6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 153);-   5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 154);-   5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 156);-   6-Trifluoroethyl-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[i]pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 159);-   7-Ethyl-8-methyl-6-(2,2,2-trifluoroethyl)-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one    (Compound 163);-   6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 170);-   (+)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 178);-   (−)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one    (Compound 179);-   8-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-5,7,7-trimethylpyrido[3,2-f]quinolin-2(1H)-one    (Compound 182);-   4-Trifluoromethyl-7-methyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one    (Compound 197);-   6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 202);-   (−)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 217); and-   (+)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one    (Compound 218).

The sequences of steps for several general schemes to synthesize thecompounds of the present invention are shown below. In each of theSchemes the R groups (e.g., R₁, R₂, etc.) correspond to the specificsubstitution patterns noted in the Examples. However, it will beunderstood by those skilled in the art that other functionalitiesdisclosed herein at the indicated positions of compounds of formulas Ithrough VIII are also potential substituents for the analogous positionson the structures within the Schemes.

Scheme I describes the synthesis of the tricyclic quinolinones ofstructure 7. Treatment of 6-nitro-2-quinolinone (structure 1) with alkylhalide such as 2-iodopropane in the presence of CsF followed by apalladium catalyzed hydrogenation provide aminoquinoline of structure 2.Copper catalyzed coupling reaction of structure 2 and propargyl acetatesuch as structure 3 followed by a copper catalyzed cyclizationregioselectively afford tricyclic quinoline derivatives of structure 4.Reduction of dihydroquinolines of structure 4 with NaBH₄ givestetrahydroquinolines of structure 5. Acid catalyzed hydrolysis ofstructure 5 provides quinolinones of structure 6. Selective alkylationat 8-position with an aldehyde or acid in the presence of a reducingagent such as NaBH₄ afford compounds of structure 7.

Scheme II describes the synthesis of angular and linear indole/indolineanalogues of structures 13–17. Treatment of 6-amino-2-quinolinones ofstructure 8 with NaNO₂ in strongly acidic conditions such asconcentrated HCl generates hydrazines of structure 9. Reaction ofcompound of structure 9 with a ketone such as structure 10 in acidicconditions affords a mixture of pyrroloquinolinones of structures 11 and12, which can be separated by chromatography. Reductive alkylation ofthe indole nitrogen atom in structure 11 or 12 with an acid or aldehydein the presence of a reducing agent such as NaBH₄ results in theformation of the reduced and alkylated products of structure 13 or 14.Oxidation of structure 13 or 14 provides analogues of structure 15, 16or 17.

Scheme III describes side chain manipulation of compounds of structure18. Treatment of compounds of structure 18 with an oxidating reagentsuch as DDQ or MnO₂ affords products of structure 19. Acylation ofcompounds of structure 19 with acetyl anhydride in the presence of DMAPgenerates compounds of structures 20 and 23. Compounds of structure 21is a by-product of the acylation reaction. Treatment of compounds ofstructure 19 with HCl in methanol gives the ether products of structure22.

Scheme IV describes the preparation of tricyclic compounds of structure26 by Fischer indole synthesis. Treatment of the 5-aminoquinolinone ofstructure 24 with NaNO₂ in acidic conditions provides the hydrazineintermediates of structure 25. Condensation of the hydrazine (structure25) and a ketone of structure 10 followed by acid catalyzed cyclizationafford compounds of structure 26.

Scheme V describes the preparation of tricyclic analogues from6-aminoquinolinones of structure 8. Skraup reaction of an aminoquinolineof structure 8 in acetone at high temperature affords compounds ofstructures 27 or 28 that depends on the substituent R₁. Treatment ofcompounds of structure 27 under a reductive alkylation condition such asNaBH₄ in TFA provides compounds of structure 29. Condensation of theaminoquinolines of structure 8 with1,1,1,5,5,5-hexafluoro-2,4-pentadione affords compounds of structure 30.

Scheme VI describes the synthesis of the tricyclic compounds ofstructures 34 and 34a. Nitration of a tetrahydroquinoline of structure31 provides compounds of structure 32. Palladium catalyzed hydrogenationof compounds of structure 32 followed by the Knorr reaction afford themixture compounds of structures 33 and 33a. Selective alkylation ofcompounds of structures 33 and 33a gives compounds of structures 34 and34a.

Scheme VII describes the synthesis of the tricyclic pyranoquinolines ofstructures 39 and 41. Alkylation of 3-nitrophenols of structure 35 givescompounds of structure 36. Thermal cyclization of the propargyl ethersof structure 36 affords the chromenes of structure 37. Reduction of thenitro group by hydrogenation provides the aminochromans of structure 38.An alternate route starts with reduction of the nitro group in compoundsof structure 36 with zinc powder followed by acylation to give thecompound of structure 36a. Cyclization at high temperature, followed bypalladium catalyzed hydrogenation, provides the chroman of structure38a. Hydrolysis of the acetyl group affords aminochroman of structure38. Treatment of compounds of structure 38 with a ketoester such asethyl 4,4,4-trifluoro-3-ketobutyrate under Knorr condition givescompounds of structures 39 and 40. In the case when the diketone ofstructure 42a is used, a quinoline of structure 42 is the product.Methylation of compounds of structure 39 with iodomethane and sodiumhydride affords compounds of structure 41.

Scheme VIII describes the synthesis of the tricyclic coumarins ofstructure 47. Annulation to form compounds of structure 44 isaccomplished by heating 1,3-resorcinol and 3,3-dimethylacrylic acid inTFA. Grignard addition to chromenones of structure 44 affords compoundsof structure 45, which is dehydrated under acidic condition to givechromenes of structure 46. Treatment of the hydroxychromenes ofstructure 46 with a ketoester such as ethyl 4,4,4-trifluoroacetoacetatein the presence of POCl₃ affords compounds of structure 47.

Scheme IX describes the general procedure to convert the 2-quinolinonederivatives to the typical 2-substituted quinoline derivatives.Treatment of compounds of structures 48 and 49 with a haloalkyl in thepresence of a catalyst such as CsF produces the corresponding 2-alkoxyquinoline compounds of structures 50 and 51. Treatment of compounds ofstructures 48 and 49 with an acyl halide in the presence of a base, suchas triethylamine, affords the 2-acyloxy quinolines of structures 52 and53.

The compounds of the present invention also include racemates,stereoisomers, optically pure enantiomers and mixtures of saidcompounds, including isotopically-labeled and radio-labeled compounds.Such isomers can be isolated by standard resolution techniques,including fractional crystallization and chiral column chromatography.

As noted above, the androgen receptor modulator compounds of the presentinvention can be combined in a mixture with a pharmaceuticallyacceptable carrier to provide pharmaceutical compositions useful fortreating the biological conditions or disorders noted herein inmammalian and particularly in human patients. The particular carrieremployed in these pharmaceutical compositions may take a wide variety offorms depending upon the type of administration desired. Suitableadministration routes include enteral (e.g., oral), topical, suppositoryand parenteral (e.g., intravenous, intramuscular and subcutaneous).

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like may be employed. Due totheir ease of administration, tablets and capsules represent a desirableoral dosage form for the pharmaceutical compositions of the presentinvention.

For parenteral administration, the carrier typically will includesterile water, although other ingredients that aid in solubility orserve as preservatives, may also be included. Furthermore, injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

For topical administration, the compounds of the present invention maybe formulated using bland, moisturizing bases, such as ointments orcreams. Examples of suitable ointment bases are petrolatum, petrolatumplus volatile silicones, lanolin and water in oil emulsions such asEucerin™, available from Beiersdorf (Cincinnati, Ohio). Examples ofsuitable cream bases are Nivea™ Cream, available from Beiersdorf(Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available fromJohnson & Johnson (New Brunswick, N.J.), hydrophilic ointment (USP) andLubriderm™, available from Warner-Lambert (Morris Plains, N.J.).

The pharmaceutical compositions and compounds of the present inventiongenerally will be administered in the form of a dosage unit (e.g.,tablet, capsule, etc.). The compounds of the present invention generallyare administered in a daily dosage of from about 1 μg/kg of body weightto about 500 mg/kg of body weight. Typically, the compounds of thepresent invention are administered in a daily dosage of from about 10μg/kg to about 250 mg/kg of body weight. Most often, the compounds ofthe present invention are administered in a daily dosage of from about20 μg/kg to about 100 mg/kg body weight. As recognized by those skilledin the art, the particular quantity of pharmaceutical compositionaccording to the present invention administered to a patient will dependupon a number of factors, including, without limitation, the biologicalactivity desired, the condition of the patient and the patient'stolerance for the drug.

The compounds of this invention also have utility when labeled (e.g.,radio-labeled, isotopically-labeled and the like) as ligands for use inassays to determine the presence of AR in a cell background or extract.They are particularly useful due to their ability to selectivelyactivate androgen receptors and can therefore be used to determine thepresence of such receptors in the presence of other steroid receptors orrelated intracellular receptors.

These invention methods comprise contacting the cell or cell extractwith the compounds of the present invention which have been labeled andtesting the contacted cell or cell extract to determine the presence ofAR. Testing can be accomplished via testing for activation of androgenreceptor(s) (e.g., via elevated presence of the product of androgenmediated process(es)), via separation of the bound compound/receptorcombination and the like, which techniques are known to those of skillin the art.

Due to the selective specificity of the compounds of this invention forsteroid receptors, these compounds can be used to purify samples ofsteroid receptors in vitro. Such purification can be carried out bymixing samples containing steroid receptors with one or more of thecompounds of the present invention so that the compounds bind to thereceptors of choice and then isolating the bound ligand/receptorcombination by separation techniques which are known to those of skillin the art. These techniques include column separation, filtration,centrifugation, tagging and physical separation and antibody complexing,among others.

The compounds and pharmaceutical compositions of the present inventioncan be used in the treatment of the diseases and conditions describedherein. In this regard, the compounds and compositions of the presentinvention may prove particularly useful as modulators of male sexsteroid-dependent diseases and conditions such as the treatment ofhypogonadism, sexual dysfunction, acne, male-pattern baldness, wastingdiseases, hirsutism, prostatic hyperplasia, osteoporosis, impotence,cancer cachexia, various hormone-dependent cancers, including, withoutlimitation, prostate and breast cancer. The compounds of the presentinvention may also prove useful in male hormone replacement therapy,stimulation of hematopoiesis, male contraception and as anabolic agents.

The compounds of the present invention may be extremely potentactivators of AR, displaying 50% maximal activation of AR (e.g.,activation of AR, determined by measurement of luciferase productionlevels compared to levels achieved by dihydrotestosterone (DHT)) at aconcentration of less than 100 nM (Cotransfection assay concentration),at a concentration of less than 50 nM, at a concentration of less than20 nM, or even at a concentration of 10 nM or less. (See, for example,Biological Examples.)

Alternatively, the compounds of the present invention may be extremelypotent inhibitors of AR, displaying 50% maximal inhibition of AR (e.g.,inhibition of AR, determined by measurement of luciferase productionlevels compared to levels achieved by dibydrotestosterone (DHT)) at aconcentration of less than 100 nM (Cotransfection assay concentration),at a concentration of less than 50 nM, at a concentration of less than20 nM, or even at a concentration of 10 nM or less. (See, for example,Biological Examples.)

In one embodiment, the selective compounds of the present inventiongenerally do not display undesired cross-reactivity with other steroidreceptors, as is seen with the compound mifepristone (RU486; RousselUclaf), a known PR antagonist that displays an undesirable crossreactivity on GR and AR, thereby limiting its use in long-term, chronicadministration.

The invention will be further illustrated by reference to the followingnon-limiting Examples.

EXAMPLE 17,8-Dihydro-7,7-dimethyl-2-isopropoxy-4-trifluoromethyl-8H-pyridino[3,2-f]quinoline(Compound 101, Structure 4 of Scheme I, where R₁=R₂=methyl)

6-Amino-2-isopropoxy-4-trifluoromethylquinoline (Compound 102, Structure2 of Scheme 1):

In a 250-mL r.b. flask, a solution of4-trifluoromethyl-6-nitroquinolinone (structure 1 of Scheme I) (3.78 g,14.6 mmol) in DMF (75 mL) was treated with CsF (12.41 g, 73 mmol, 5.0equiv.) and 2-iodopropane (11.09 g, 73 mmol, 5.0 equiv). The reactionmixture was stirred at room temperature (rt) for 18 h. The reactionmixture was quenched with H₂O (100 mL) and extracted with EtOAc (3×200mL). The combined EtOAc extracts were washed with saturated aqueousNH₄Cl solution (300 mL), H₂O (300 mL) and brine (300 mL). Dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (SiO₂, 5×20 cm, 2% EtOAc in hexane as eluent) toafford 3.94 g (90%) of the 2-isopropoxyquinoline as a white solid. R_(f)0.81 (SiO₂, 10% EtOAc-hexane). ¹H NMR (400 MHz, CDCl₃) 8.93 (s, 1H),8.47 (dd, 1H, J=9.2, 2.5) 7.98 (d, 1H, J=9.2), 7.32 (s, 1H), 5.62(septet, 1H, J=6.2), 1.45 (d, 1H, J=6.2).

In a 100-mL r.b. flask, a solution of2-isopropoxy-4-trifluoromethyl-6-nitroquinolinone (1.0 g, 3.3 mmol) in a3:1 ratio of CH₂Cl₂/MeOH (40 mL) was treated with 10% Pd/C (168 mg, 16wt. % equiv). The resulting mixture was stirred under H₂ (1 atm) at rtfor 18 h. The reaction mixture was filtered through a pad of celite andthe celite cake was rinsed with MeOH (100 mL). The filtrate wasconcentrated in vacuo to give 0.85 g (95%) of compound 102 as colorlessoil that was used immediately in the next reaction without furtherpurification. R_(f) 0.27 (SiO₂, 10% EtOAc-hexane). ¹H NMR (400 MHz,CDCl₃) 7.70 (d, 1H, J=9.6) 7.13 (m, 3H), 5.49 (septet, 1H, J=6.2), 3.89(s, 2H), 1.39 (d, 1H, J=6.2).

7,8-Dihydro-7,7-dimethyl-2-isopropoxy-4-trifluoromethyl-8H-pyridino[3,2-f]quinoline(Compound 101, Structure 4 of Scheme I, where R₁=R₂=methyl).

In a 250-mL r.b. flask, a solution of compound 102 (4.55 g, 16.8 mmol)in THF (150 mL) was treated with Cu(I)Cl (0.167 g, 0.168 mmol, 10 mol %)and 2-acetoxy-2-methyl-3-butyne (structure 3 of Scheme I, whereR₁=R₂=methyl) (3.19 g, 25.3 mmol, 1.5 equiv). The reaction mixture washeated to reflux for 18 h. After cooling to rt, the reaction mixture wasfiltered through a pad of celite and the celite cake was rinsed withEtOAc (300 mL). The filtrate was washed with saturated aqueous NH₄Clsolution (150 mL), H₂O (150 mL) and brine (150 mL). Dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography (SiO₂, 5×20 cm, 5% EtOAc in hexane as eluent) toafford 4.85 g (86%) of compound 101 as a yellow-greenish solid. R_(f)0.53 (SiO₂, 10% EtOAc-hexane). ¹H NMR (400 MHz, CDCl₃) 7.57 (d, 1H,J=8.9), 7.19 (s, 1H), 6.95 (d, 1H, J=8.9), 6.91 (d, 1H, J=10), 5.50–5.43(m, 2H), 4.06 (s, 1H), 1.38 (d, 6H, J=6.2), 1.33 (s, 6H).

EXAMPLE 25,6,7,8-Tetrahydro-7,7-dimethyl-2-isopropoxy-4-trifluoromethylpyridino[3,2-f]quinoline(Compound 103, Structure 5 of Scheme I, where R₁=R₂=methyl)

In a 250-mL r.b. flask, a solution of compound 101 (3.64 g, 10.8 mmol)in TFA (50 mL) was treated with NaBH₄ caplets (4.5 g, 119 mmol, 11equiv). The reaction mixture was stirred at rt for 20 h. The reactionmixture was poured onto 200 mL of ice-water, neutralized with NaHCO₃powder to pH 7 and extracted with EtOAc (3×250 mL). The combinedextracts were washed with brine (2×200 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 5×20 cm, 5% EtOAc in hexane as eluent) to afford3.38 g (92%) of compound 103 as a yellow solid. R_(f) 0.50 (SiO₂, 10%EtOAc-hexane). ¹H NMR (400 MHz, CDCl₃) 7.56 (d, 1H, J=8.8), 7.24 (s,1H), 6.89 (d, 1H, J=8.8), 5.46 (septet, 1H, J=6.2), 3.85 (s, 1H), 3.07(t, 2H, J=6.5), 1.68 (t, 2H, J=6.5), 1.38 (d, 6H, J=6.2), 1.26 (s, 6H).

EXAMPLE 35,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one(Compound 104, Structure 6 of Scheme I, where R₁=R₂=methyl)

In a 250-mL r.b. flask, a solution of compound 103 (3.97 g, 11.7 mmol)in AcOH (50 mL) was treated with conc. HCl (50 mL). The reaction mixturewas heated to 95° C. and stirred for 4 h. After cooling to rt, thereaction mixture was poured onto ice-water, neutralized with NaHCO₃powder to pH 7 and extracted with EtOAc (3×500 mL). The combinedextracts were washed with H₂O (500 mL) and brine (500 mL), dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified byrecrystallizing from EtOAc/hexane to afford 3.42 g (98%) of compound 104as a yellow-orange solid. ¹H NMR (400 MHz, CDCl₃) 10.35 (br. s, 1H),7.27 (d, 1H, J=8.6), 7.25 (s, 1H), 6.82 (d, 1H, J=8.6), 3.80 (s, 1H),3.03 (t, 2H, J=6.5), 1.67 (t, 2H, J=6.5), 1.24 (s, 6H).

EXAMPLE 45,6,7,8-Tetrahydro-7,7-diethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one(Compound 105, Structure 6 of Scheme I, where R₁=R₂=ethyl)

This compound was prepared in a similar fashion as described in Examples1, 2 and 3 from compound 102 and 2′,2′-diethylpropargyl acetate(structure 3 of Scheme I, where R₁=R₂=ethyl). Spectral data for compound105: ¹H NMR (400 MHz, CDCl₃) 7.22 (s, 1H), 7.14 (d, J=8.7, 1H), 6.83 (d,J=8.7, 1H), 3.78 (bs, 1H), 2.98 (t, J=6.5, 2H), 1.67 (t, J=6.5, 2H),1.49 (q, J=7.4, 6H), 0.89 (t, J=7.4, 4H).

EXAMPLE 57,8-Dihydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one(Compound 106, Structure 4a of Scheme I, where R₁=R₁=hydrogen)

This compound was prepared in a similar fashion as that described inExample 3 from compound 101. Spectral data for compound 106: ¹H NMR (500MHz, acetone-d₆) 11.0 (bs, 1H), 7.24 (d, J=8.8, 1H), 7.05 (d, J=8.8,1H), 6.98 (s, 1H), 6.78 (d, J=10.3, 1H), 5.62 (bs, 1H), 5.558 (dd,J=9.8, 1.9, 1H), 1.30 (s, 6H).

EXAMPLE 65,6,7,8-Tetrahydro-7,7,8-trimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one(Compound 107, Structure 7 of Scheme I, where R₁=R₂=R₃=methyl)

In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of SchemeI, where R₁=R₂=methyl, 41 mg, 0.15 mmol) in MeOH (5 mL) was treated withformaldehyde (5 mL, 37 wt. % solution in water), AcOH (2 mL) and NaCNBH₃(excess). The reaction mixture was stirred at rt for 24 h. The reactionmixture was poured onto ice-water (50 mL), neutralized with NaHCO₃powder to pH 7 and extracted with EtOAc (3×50 mL). The combined extractswere washed with H₂O (50 mL) and brine (50 mL), dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 1×20 cm, 50% EtOAc in hexane as eluent) to afford32 mg (75%) of 107 as an orange solid: R_(f) 0.40 (SiO₂,2:1=EtOAc:hexane); ¹H NMR (400 MHz, CDCl₃) 11.45 (br. s, 1H), 7.23 (d,1H, J=9.1), 7.22 (s, 1H), 7.05 (d, 1H, J=9.1), 2.97 (t, 2H, J=6.2), 2.88(s, 3H), 1.71 (t, 2H, J=6.2), 1.27 (s, 6H).

EXAMPLE 78-Ethyl-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethylpyridino[3,2-f]quinolin-2(1H)-one(Compound 108, Structure 7 of Scheme I, where R₁=R₂=methyl, R₃=ethyl)

In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of SchemeI, where R₁=R₂=methyl) (35.3 mg, 0.119 mmol) in MeOH (5 mL) was treatedwith acetaldehyde (2 mL), AcOH (2 mL) and NaCNBH₃ (excess). The reactionmixture was stirred at rt for 24 h. The reaction mixture was poured ontoice-water (50 mL), neutralized with NaHCO₃ powder to pH 7 and extractedwith EtOAc (3×50 mL). The combined extracts were washed with H₂O (50 mL)and brine (50 mL), dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by flash column chromatography (SiO₂, 1×20 cm,50% EtOAc in hexane as eluent) to afford 19.1 mg (50%) of compound 108as an orange solid: R_(f) 0.51 (SiO₂,2:1=EtOAc:hexane); ¹H NMR (400 MHz,CDCl₃) 11.42 (br. s, 1H), 7.23 (d, 1H, J=9.2), 7.21 (s, 1H), 7.05 (d,1H, J=9.2), 3.38 (q, 2H, J=7.0), 2.97 (t, 2H, J=6.2), 1.71 (t, 2H,J=6.2), 1.27 (s, 6H), 1.17 (t, 3H, J=7.0).

EXAMPLE 85,6,7,8-Tetrahydro-7,7-dimethyl-4-trifluoromethyl-8-propylpyridino[3,2-f]quinolin-2(1H)-one(Compound 109, Structure 7 of Scheme I, where R₁=R₂=methyl, R₃=propyl)

In a 25-mL r.b. flask, a solution of compound 104 (structure 6 of SchemeI, where R₁=R₂=methyl) (34 mg, 0.115 mmol) in MeOH (5 mL) was treatedwith propionaldehyde (2 mL), AcOH (2 mL) and NaCNBH₃ (excess). Thereaction mixture was stirred at rt for 24 h. The reaction mixture waspoured onto ice-water (50 mL), neutralized with NaHCO₃ powder to pH 7and extracted with EtOAc (3×50 mL). The combined extracts were washedwith H₂O (50 mL) and brine (50 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 1×20 cm, 50% EtOAc in hexane as eluent) to afford13.2 mg (34%) of compound 109 as an orange solid: R_(f) 0.51 (SiO₂,2:1=EtOAc:hexane); ¹H NMR (400 MHz, CDCl₃) 10.89 (br. s, 1H), 7.28 (d,1H, J=9.0), 7.21 (s, 1H), 7.01 (d, 1H, J=9.0), 3.20 (t, 2H, J=7.7), 2.96(t, 2H, J=6.1), 1.70 (t, 2H, J=6.1), 1.60–1.50 (m, 2H), 1.25 (s, 6H),0.92 (t, 3H, J=7.3).

EXAMPLE 98-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-7,7-dimethyl-4-trifluoromethyl-pyridino[3,2-f]quinolin-2(1H)-one(Compound 110, Structure 7 of Scheme I, where R₁=R₂=methyl,R₃=2,2,2-trifluoroethyl)

In a 100-mL r.b. flask, a solution of compound 104 (structure 6 ofScheme I, where R₁=R₂=methyl) (0.59 g, 2.0 mmol) in TFA (15 mL) wastreated with NaBH₄ (6.0 g). The reaction mixture was heated to 95° C.and stirred for 6 h. The reaction mixture was diluted with EtOAc (50 mL)and poured onto ice-water (50 mL), neutralized with NaHCO₃ powder to pH7 and extracted with EtOAc (2×100 mL). The combined extracts were washedwith H₂O (150 mL) and brine (150 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 3×20 cm, 50% EtOAc in hexane as eluent) to afford0.62 g (81%) of compound 110 as a yellow solid: R_(f) 0.56 (SiO₂,2:1=EtOAc:hexane); ¹H NMR (400 MHz, Acetone-d₆) 11.0 (s, 1H), 7.43 (d,1H, J=9.2), 7.35 (d, 1H, J=9.2), 7.05 (s, 1H), 4.22 (q, 2H, J=9.0), 2.98(t, 2H, J=6.1), 1.77 (t, 2H, J=6.1), 1.31 (s, 6H).

EXAMPLE 10 6-Hydrazino-4-trifluoromethylquinolin-2(1H)-one (Compound111, Structure 9 of Scheme II, where R₁=trifluoromethyl)

In a 250 mL r.b. flask a suspension of6-amino-4-trifluoromethylquinolin-2(1H)-one (structure 8 of Scheme II,where R₁=trifluoromethyl) (2.28 g, 10 mmol) in 10 mL conc. HCl wascooled to −1° C. and a solution of NaNO₂ (0.40 g, 12 mmol) in water (5mL) was added dropwise in 20 min. The dark yellow suspension was stirredat −1° C. for 1 h and then a solution of SnCl₂.2H₂O (5.2 g, 15 mmol) inconc. HCl (10 mL) was added dropwise in 10 min. The light yellowsuspension of the hydrazine was stirred at −1° C. for 2 h and then useddirectly or kept in a refrigerator at −1° C. until it was used (thecrude compound can be stored for at least one month withoutdecomposition).

EXAMPLE 116-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one (Compound112, Structure 11 of Scheme II, where R₃=H R₂=methyl,R₁=trifluoromethyl)

To the crude suspension of compound 111 (˜0.4 M) in aqueous HCl wasadded a solution of acetone (structure 10 of Scheme II, 2–5 eq.) in anequal volume of EtOH and the mixture was heated in a sealed tube at 130°C. for 2 h. Then the mixture was diluted with an equal volume of waterwhile still hot and allowed to cool to rt. The precipitate was filteredand washed with water to give compound 112 as a yellow solid: ¹H NMR(500 MHz, acetone-d₆) 11.1 (bs, 1 H), 10.6 (bs, 1 H), 7.69 (d, J=8.8, 1H), 7.25 (d, J=8.8, 1 H), 6.94 (s, 1 H), 6.64 (s, 1 H), 2.51 (s, 3 H).

EXAMPLE 125-Isopropyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 113, Structure 11 of Scheme II, where R₃=isopropyl, R₂=methyl,R₁=trifluoromethyl)

To the crude suspension of compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) (˜0.4 M) in aqueous HCl was added a solution of aketone (structure 10 of Scheme II) (2–5 eq.) in an equal volume of EtOHand the mixture was refluxed for 2 h. Then the mixture was diluted withan equal volume of water while still hot and allowed to cool to rt. Theprecipitate was filtered and washed with water to give the indole as amixture of regioisomers. The ratio of angular and linear isomers wasdetermined by ¹H NMR. The mixture of regioisomers could be separated bychromatography (Silica gel, hex/EtOAc 1:1 to 0:1 gradient). Spectra datafor compound 113: ¹H NMR (500 MHz, DMSO-d₆) 12.2 (bs, 1H), 11.3 (bs,1H), 7.52 (d, J=8.8, 1H), 7.03 (d, J=8.8, 1H), 6.87 (s, 1H), 3.30–3.24(m, 1H), 6.64 (s, 1H), 2.48 (s, 3H), 1.22 (d, J=6.8, 6H).

EXAMPLE 135-Allyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 114, Structure 11 of Scheme II, where R₃=allyl, R₂=methyl,R₁=trifluoromethyl)

This compound was prepared in a similar fashion as that described inExample 12 from compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and 5-hexen-2-one (structure 10 of Scheme II) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) 12.3 (bs, 1H), 11.5 (bs, 1H),7.59 (d, J=8.8, 1H), 7.10 (d, J=8.8, 1H), 6.89 (s, 1H), 5.82–5.76 (m,1H), 4.85 (dd, J=10.8, 2.0, 1H), 4.76 (dd, J=17.1, 2.0, 1H), 3.50 (d,J=5.9, 2H), 2.33 (s, 3H).

EXAMPLE 145-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H1)-one(Compound 115, Structure 11 of Scheme II, where R₃=4-methoxyphenyl,R₂=methyl, R₁=trifluoromethyl)

This compound was prepared in a similar fashion as that described inExample 12 from compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and 1-(4-methoxyphenyl)acetone (structure 10 ofScheme II) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) 12.3 (bs, 1 H),11.7 (bs, 1 H), 7.64 (d, J=8.8, 1 H), 7.14 (d, J=8.8, 1 H), 7.06 (d,J=8.8, 2 H), 6.91 (d, J=8.8, 2 H), 6.68 (s, 1 H), 3.77 (s, 3 H), 2.22(s, 3 H).

EXAMPLE 155-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 116, Structure 11 of Scheme II, whereR₃=3-trifluoromethylphenyl, R₂=methyl, R₁=trifluoromethyl)

This compound was prepared in a similar fashion as that described inExample 12 from compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and 1-(3-trifluoromethylphenyl)acetone (structure 10of Scheme II) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) 12.4 (bs,1H), 11.9 (bs, 1H), 7.69 (d, J=8.8, 1H), 7.62–7.59 (m, 2H), 7.53 (bd,J=4.9, 1H), 7.41 (s, 1H), 7.21 (d, J=8.8, 2H), 6.73 (s, 1 H), 2.27 (s,3H).

EXAMPLE 164-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 117, Structure 11 of Scheme II, where R₃, R₂=—CH₂CH₂CH₂—,R₁=trifluoromethyl

This compound was prepared in a similar fashion as that described inExample 12 from compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and cyclopentanone (structure 10 of Scheme II) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) 11.6 (bs, 1H), 10.5 (bs, 1H),7.73 (d, J=8.8, 1H), 7.26 (d, J=8.8, 1H), 6.92 (s, 1H), 3.05–3.02 (m,2H), 2.91–2.88 (m, 2H), 2.47–2.43 (m, 2H).

EXAMPLE 174-Trifluoromethyl-5,6,7,8,9,10-hexahydrocycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 118, Structure 11 of Scheme II, where R₃, R₂=—(CH₂)₅—,R₁=trifluoromethyl)

This compound was prepared in a similar fashion as that described inExample 12 from compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and cycloheptanone (structure 10 of Scheme II) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) 11.4 (bs, 1H), 10.5 (bs, 1H),7.63 (d, J=8.3, 1H), 7.17 (d, J=8.3, 1 H), 6.91 (s, 1H), 2.98–2.94 (m, 2H), 2.91–2.87 (m, 2 H), 1.92–1.86 (m, 2H). 1.81–1.75 (m, 2H), 1.69–1.63(m, 2H).

EXAMPLE 18(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 119, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₁=2,2,2-trifluoroethyl)

To a solution of compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—, 1.30 g, 4.45 mmol) in TFA (40 mL) in a 250 mL r.b. flaskwas added a pellet (˜0.75 g, 22 mmol) of NaBH₄. Two more pellets ofNaBH₄ were added with 30 min intervals and the mixture was stirred at rtfor 16 h until the starting material was consumed. Water was carefullyadded (˜150 mL) and the yellow precipitate was filtered and washed withwater. The yellow solid was purified by column chromatography (Silicagel, hex:EtOAc, 7:3) to give compound 119 (1.27 g, 76%) as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 12.3 (bs, 1H), 7.28 (d, J=8.8, 1H), 7.19(s, 1H), 6.87 (d, J=8.8, 1H), 4.30 (d, J=4.9, 2H), 4.06–4.02 (m, 2H),3.74–3.58 (m, 2H), 2.15–2.13 (m, 2H), 1.77–1.66 (m, 3H), 1.58–1.53 (m,1H).

EXAMPLE 19(±)-6,6a,7,8,9,9a(cis)-Hexahydro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[i]pyrrolo[2,3-g]quinolin-2(1H)-one(Compound 120, Structure 14 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was isolated as a regioisomer of compound 119 (structure13 of Scheme II, where R₃, R₂=—(CH₂)₃—, R₁=trifluoromethyl,R₄=trifluoroethyl) in the same reaction process as a yellow solid: ¹HNMR (500 MHz, CDCl₃) 12.4 (bs, 1H), 7.18 (s, 1H), 7.03 (s, 1H), 6.64 (s,1H), 4.35 (dd, J=6.3, 6.3, 1H), 3.89–3.85 (m, 1H), 3.76 (q, J_(H-F)=9.3,1H), 2.14–2.06 (m, 1H), 1.98–1.92 (m, 1H), 1.888–1.82 (m, 1H), 1.79–1.70(m, 2H), 1.59–1.53 (m, 1H).

EXAMPLE 20(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 121, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=ethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and acetic acid. ¹H NMR (500 MHz, CDCl₃) 12.0 (bs, 1H),7.21 (d, J=8.3, 1H), 7.19 (s, 1H), 6.87 (d, J=8.8, 1H), 4.30 (d, J=4.9,2H), 4.06–4.02 (m, 2H), 3.74–3.58 (m, 2H), 2.15–2.13 (m, 2H), 1.77–1.66(m, 3H), 1.58–1.53 (m, 1H).

EXAMPLE 21(±)-6,6a,7,8,9,9a(cis)-Hexahydro-6-ethyl-4-trifluoromethylcyclopentano-[i]pyrrolo[2,3-g]quinolin-2(1H)-one(Compound 122, Structure 14 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=ethyl)

This compound was isolated as a regioisomer of compound 121 (Structure13 of Scheme II, where R₃, R₂=—(CH₂)₃—, R₁=trifluoromethyl, R₄=ethyl) inthe same reaction described in Example 20 as a yellow solid: ¹H NMR (500MHz, CDCl₃) 11.9 (bs, 1H), 7.08 (s, 1H), 6.99 (s, 1 H), 6.41 (d, J=2.0,1 H), 4.30–4.27 (m, 1H), 3.79–3.75 (m, 1H), 3.34 (dq, J=7.3, 7.3, 1H),3.21 (dq, J=7.3, 7.3, 1H), 2.08–2.01 (m, 1H), 1.89–1.86 (m, 1H),1.82–1.79 (m, 1H), 1.72–1.65 (m, 2 H), 1.58–1.52 (m, 1H), 1.18 (t,J=7.3, 3H).

EXAMPLE 22(±)-5,6-Dihydro-5,6-cis-dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3.2-f]quinolin-2(1H)-one(Compound 123, Structure 13 of Scheme II, where R₃=R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 2-butanone. ¹H NMR (500 MHz, CDCl₃) 12.3 (bs,1H), 7.32 (d, J=8.8, 1H), 7.21 (s, 1H), 6.95 (d, J=8.8, 1H), 3.75–3.53(m, 4H), 1.38 (d, J=6.8, 3H), 0.98 (d, J=6.8, 3H).

EXAMPLE 23(±)-7,8-Dihydro-7,8-cis-dimethyl-6-(2,2,2-trifluoroethyl)-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one(Compound 124, Structure 14 of Scheme II, where R₃=R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was isolated as a regioisomer of compound 123 (Structure13 of Scheme II, where R₃=R₂=methyl, R₁=trifluoromethyl,R₄=trifluoroethyl) in the same reaction described in Example 22 as ayellow solid: ¹H NMR (500 MHz, CDCl₃) 12.1 (bs, 1H), 7.13 (d, J=1.5,1H), 7.04 (s, 1H), 6.76 (s, 1H), 3.75–3.60 (m, 2H), 3.33 (dq, J=6.3,5.9, 1H), 2.95 (dq, J=7.3, 5.9, 1H), 1.41 (d, J=7.3, 3H), 1.39 (d,J=6.3, 3H).

EXAMPLE 24(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one(Compound 125, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃,—R₁=trifluoromethyl, R₄=propyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and propionic acid. ¹H NMR (500 MHz, CDCl₃) 10.4 (bs, 1H),7.31 (dd, J=8.8, 1.8, 1H), 7.20 (s, 1H), 6.78 (d, J=8.8, 1H), 4.28–4.26(m, 1H), 3.96–3.95 (m, 1H), 3.14–3.05 (m, 2H), 2.06–2.03 (m, 2H),1.72–1.51 (m, 6H), 0.95 (t, J=7.3, 3H).

EXAMPLE 25(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-furanylmethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 126, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=3-furanylmethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and 3-furoic acid. ¹H NMR (500 MHz, CDCl₃) 12.2 (bs, 1H),7.36–7.35 (m, 1H), 7.29 (s, 1H), 7.22 (d, J=8.8, 1H), 7.16 (s, 1 H),6.82 (d, J=8.3, 1H), 6.26 (d, J=1.0, 1H), 4.27–4.22 (m, 2H), 4.08 (d,J=16.1, 1H), 3.97–3.91 (m, 1H), 2.12–2.08 (m, 1H), 2.03–2.01 (m, 1H),1.72–1.70 (m, 3H), 1.60–1.58 (m, 1H).

EXAMPLE 26(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 127, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=3-thiophenemethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and 3-thiophenecarboxylic acid. ¹H NMR (500 MHz, CDCl₃)10.9 (bs, 1H), 7.29 (dd, J=5.4, 2.9, 1H), 7.13 (s, 1H), 7.07 (d, J=8.3,1H), 7.06 (s, 1H), 6.96 (dd, J=5.4, 1.5, 1H), 7.12–7.04 (m, 1H), 6.72(d, J=8.3, 1H), 4.38 (d, J=16.1, 1H), 4.26 (d, J=16.1, 1H), 4.27–4.25(m, 1H), 3.98–3.94 (m, 1H), 2.16–2.07 (m, 1H), 2.04–2.22 (m, 1H),1.78–1.68 (m, 3H), 1.60–1.54 (m, 1H).

EXAMPLE 27(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 128, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=2-methylpropyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and isobutyric acid. ¹H NMR (500 MHz, CDCl₃) 12.2 (bs, 1H),7.20 (d, J=8.8, 1H), 7.15 (s, 1H), 6.74 (d, J=8.8, 1H), 4.22–4.19 (m,1H), 3.98–3.93 (m, 1H), 2.93 (dd, J=14.3, 7.3, 1H), 2.81 (dd, J=14.3,7.9, 1H), 2.14–2.00 (m, 3H), 1.72–1.63 (m, 3H), 1.56–1.52 (m, 1 H), 0.97(d, J=6.7, 3H), 0.92 (d, J=6.7, 3H).

EXAMPLE 28(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 129, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=2,2,2-chlorodifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and chlorodifluoroacetic acid. ¹H NMR (500 MHz, CDCl₃) 12.3(bs, 1H), 7.38 (d, J=8.8, 1 H), 7.29 (s, 1H), 7.00 (d, J=8.8, 1H),4.46–4.44 (m, 1H), 4.09–4.05 (m, 1H), 3.94–3.81 (m, 2H), 2.21–2.12 (m,2H), 1.81–1.74 (m, 2H), 1.69–1.63 (m, 1H), 1.56–1.52 (m, 1 H).

EXAMPLE 29(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 130, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and cyclopropanecarboxylic acid. ¹H NMR (500 MHz, CDCl₃)12.4 (bs, 1H), 7.25 (d, J=8.8, 1H), 7.16 (s, 1H), 6.84 (d, J=8.8, 1H),4.41–4.38 (m, 1H), 3.97–3.92 (m, 1 H), 3.18 (dd, J=14.9, 5.5, 1H), 2.90(dd, J=14.9, 7.3, 1H), 2.14–2.04 (m, 2H), 1.78–1.66 (m, 3H), 1.55–1.49(m, 1H), 0.97–0.92 (m, 1H), 0.61–0.55 (m, 1H), 0.53–0.47 (m, 1H),0.28–0.22 (m, 1H), 0.19–0.14 (m, 1H).

EXAMPLE 30(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2-dimethoxyethyl)-4-trifluoromethyl-cyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 131, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=2,2-dimethoxyethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 117 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₃—) and dimethoxyacetaldehyde. ¹H NMR (500 MHz, CDCl₃) 11.1(bs, 1H), 7.14 (s, 1H), 7.12 (d, J=8.8, 1H), 6.91 (d, J=8.8, 1H), 4.43(dd, J=5.9, 4.4, 1H), 4.31–4.30 (m, 1H), 3.94–3.93 (m, 1H), 3.41 (s,6H), 3.30 (dd, J=15.1, 5.9, 1H), 3.21 (dd, J=15.1, 4.4, 1H), 2.12–2.09(m, 2H), 1.72–1.55 (m, 4H).

EXAMPLE 31(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 132, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₄—,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and cyclohexanone. ¹H NMR (500 MHz, CDCl₃) 12.1 (bs,1H), 7.29 (d, J=8.8, 1H), 7.19 (s, 1H), 7.02 (d, J=8.8, 1H), 3.70–3.60(m, 2H), 3.56 (m, 1H), 3.41–3.38 (m, 1H), 2.14 (d, J=14.6, 1H),1.75–1.67 (m, 3H), 1.61–1.56 (m, 2H), 1.31–1.25 (m, 1H), 1.05–0.98 (m,1H).

EXAMPLE 32(±)-4c,5,6,7,8,9,9a(cis),10-Octahydro-10-(2,2,2-trifluoroethyl)-4-trifluoromethyl-cycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 133, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₅—,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 118 (structure 11 of Scheme II, where R₃,R₂=—(CH₂)₅—). ¹H NMR (500 MHz, CDCl₃) 12.0 (bs, 1H), 7.32 (d, J=8.8,1H), 7.25 (s, 1H), 6.98 (d, J=8.8, 1H), 3.96–3.91 (m, 1H), 3.73–3.62 (m,3H), 2.36–2.26 (m, 2H), 1.93–1.86 (m, 3H), 1.78–1.69 (m, 2H), 1.48–1.36(m, 3H).

EXAMPLE 33(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 134, Structure 13 of Scheme II, where R₃=methyl, R₂=ethyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and 3-pentanone. ¹H NMR (500 MHz, CDCl₃) 11.6 (bs,1H), 7.26 (d, J=8.3, 1H), 7.15 (s, 1H), 6.74 (d, J=8.3, 1H), 4.25 (dd,J=7.3, 3.4, 1H), 3.96–3.91 (m, 1H), 3.29 (dq, J=7.3, 1H), 3.16 (dq,J=7.3, 7.3, 1H), 1.965–1.85 (m, 2H), 1.08 (t, J=7.3, 3H), 0.98 (d,J=6.3, 3H).

EXAMPLE 34(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 135, Structure 13 of Scheme II, where R₃=butyl, R₂=methyl,R₁=trifluoromethyl, R₁=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (structure 9 of Scheme II, whereR₁=trifluoromethyl) and 2-heptanone. ¹H NMR (500 MHz, CDCl₃) 12.1 (bs,1H), 7.29 (d, J=8.8, 1H), 7.20 (s, 1H), 6.94 (d, J=8.8, 1H), 3.76–3.68(m, 1H), 3.67–3.57 (m, 2H), 3.47–3.43 (m, 1H), 1.74–1.66 (m, 1H), 1.44(d, J=6.8, 3H), 1.36–1.29 (m, 1H), 1.28–1.20 (m, 1H), 1.20–1.12 (m, 3H),0.81 (t, J=7.3, 3 H).

EXAMPLE 35(±)-5,6-cis-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 136, Structure 13 of Scheme II, where R₃=4-nitrophenyl,R₂=methyl, R₁=trifluoromethyl, R₁=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 4-nitrophenylacetone. ¹H NMR (500 MHz, CDCl₃)12.1 (bs, 1H), 8.05 (d, J=8.3, 2H), 7.47 (d, J=8.8, 1H), 7.13 (d, J=8.8,1H), 7.13 (s, 1H), 6.90 (bs, 2H), 4.79 (d, J=7.3, 1H), 4.11 (dq, J=7.3,6.3, 1H), 3.78–3.61 (m, 2H), 0.96 (d, J=6.3, 3H).

EXAMPLE 36(±)-5,6-cis-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 137, Structure 13 of Scheme II, whereR₃=4-dimethylaminophenyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 4-dimethylaminophenylacetone. ¹H NMR (500 MHz,CDCl₃) 12.3 (bs, 1H), 7.40 (d, J=8.8, 1H), 7.09 (s, 1H), 7.06 (d, J=8.8,1H), 6.56–6.52 (m, 4H), 4.59 (d, J=7.3, 1H), 3.96 (dq, J=7.3, 6.3, 1H),3.77–3.67 (m, 1H), 3.67–3.57 (m, 1H), 2.86 (s, 6H), 0.95 (d, J=6.3, 3H).

EXAMPLE 37(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 138, Structure 13 of Scheme II, where R₃=4-methoxyphenyl,R₂=methyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 115 (Structure 11 of Scheme II, whereR₃=4-methoxyphenyl, R₂=methyl, R₁=trifluoromethyl). ¹H NMR (500 MHz,CDCl₃) 11.6 (bs, 1H), 7.36 (d, J=8.8, 1H), 7.09 (s, 1H), 7.07 (d, J=8.8,1H), 6.71 (d, J=8.8, 2H), 6.63 (bs, 2H), 4.63 (d, J=7.3, 1H), 3.99 (dq,J=7.3, 6.3, 1H), 3.74–3.58 (m, 2H), 3.73 (s, 3H), 0.94 (d, J=6.3, 3H).

EXAMPLE 38(±)-5,6-cis-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 139, Structure 13 of Scheme II, whereR₃=3-trifluoromethylphenyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 116 (Structure 11 of Scheme II, whereR₃=3-trifluoro-methylphenyl, R₂=methyl, R₁=trifluoromethyl). ¹H NMR (500MHz, CDCl₃) 12.8 (bs, 1H), 7.51 (d, J=8.8, 1H), 7.43 (d, J=7.8, 1H),7.30–7.26 (m, 1H), 7.14 (s, 1H), 7.12 (d, J=8.8, 1H), 7.12–7.04 (m, 1H),6.92–6.78 (bs, 1H), 4.74 (d, J=6.8, 1H), 4.08 (dq, J=6.8, 6.3, 1H),3.78–3.60 (m, 2H), 0.93 (d, J=6.3, 3H).

EXAMPLE 39(±)-5,6-cis-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 140, Structure 13 of Scheme II, where R₃=4-fluorophenyl,R₂=methyl, R₁=trifluoromethyl, R₁=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 4-fluorophenylacetone. ¹H NMR (500 MHz, CDCl₃)10.6 (bs, 1H), 7.28 (d, J=8.8, 1H), 7.08 (s, 1H), 7.07 (d, J=8.8, 1H),6.88–6.85 (m, 2H), 6.68 (bs, 2H), 4.66 (d, J=6.8, 1H), 4.01 (dq, J=6.8,6.3, 1H), 3.73–3.67 (m, 2H), 3.67–3.60 (m, 1H), 0.94 (d, J=6.3, 3H).

EXAMPLE 40(±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 141, Structure 13 of Scheme II, where R₃=phenyl, R₂=H,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and phenylacetaldehyde. ¹H NMR (500 MHz, CDCl₃) 12.6(bs, 1H), 7.48 (d, J=8.8, 1H), 7.20–7.14 (m, 3H), 7.14 (s, 1H), 7.05 (d,J=8.8, 1H), 6.76–6.74 (m, 2H), 4.89 (d, J=8.3, 2H), 3.93 (dd, J=8.3,8.3, 1H), 3.84–3.77 (m, 1H), 3.64–3.56 (m, 1H), 3.55 (d, J=8.8, 1H).

EXAMPLE 41(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 142, Structure 13 of Scheme II, where R₃=4-methoxyphenyl,R₂=methyl, R₁=trifluoromethyl, R₄=H)

This compound was isolated as a minor product from the same reactiondescribed in Examples 37. ¹H NMR (500 MHz, CDCl₃) 12.0 (bs, 1H), 7.32(d, J=8.8, 1H), 7.09 (s, 1H), 7.14 (d, J=8.8, 1H), 7.08 (s, 1H), 6.73(d, J=8.8, 2H), 6.65 (bs, 2H), 4.60 (d, J=7.3, 1H), 4.21 (dq, J=7.3,6.3, 1H), 3.73 (s, 3H), 1.25 (bs, 1H), 0.92 (d, J=6.3, 3H).

EXAMPLE 42(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 143, Structure 13 of Scheme II, where R₃=4-methoxyphenyl,R₂=methyl, R₁=trifluoromethyl, R₄=2,2-dimethoxyethyl)

This compound was prepared in a similar fashion as that described inExample 30 from Compound 115 (Structure 11 of Scheme II, whereR₃=4-methoxyphenyl, R₂=methyl, R₁=trifluoromethyl). ¹H NMR (500 MHz,CDCl₃) 11.7 (bs, 1H), 7.33 (d, J=8.8, 1H), 7.17 (d, J=8.8, 1H), 7.07 (s,1H), 6.69 (bd, J=8.8, 2H), 6.63 (bs, 2H), 4.58 (d, J=7.3, 1H), 4.31 (dd,J=5.9, 3.9, 1H), 3.93 (dq, J=7.3, 6.8, 1H), 3.73 (s, 3H), 3.41 (s, 3H),3.37 (s, 3H), 3.27 (dd, J=15.1, 3.9, 1H), 3.22 (dq, J=15.1, 5.9, 1H),0.92 (d, J=6.8, 3H).

EXAMPLE 43(±)-5,6-cis-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 144, Structure 13 of Scheme II, where R₃=isopropyl, R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 113 (Structure 11 of Scheme II, whereR₃=isopropyl, R₂=methyl, R₁=trifluoromethyl). ¹H NMR (500 MHz, CDCl₃)11.6 (bs, 1H), 7.25 (d, J=8.3, 1H), 7.17 (s, 1H), 6.93 (d, J=8.3, 1H),3.80 (dq, J=6.8, 6.8, 1H), 3.69–3.52 (m, 2H), 3.40 (dd, J=6.8, 5.4, 1H),1.96–1.88(m, 1H), 1.53 (d, J=6.8, 3H), 0.83 (d, J=6.8, 1H), 0.79 (d,J=7.3, 3H).

EXAMPLE 44(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 145, Structure 13 of Scheme II, where R₃=ethyl, R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 2-pentanone. ¹H NMR (500 MHz, CDCl₃) 12.3 (bs,1H), 7.29 (d, J=8.8, 1H), 7.23 (s, 1H), 6.98 (d, J=8.8, 1H), 3.84–3.78(m, 1H), 3.71–3.59 (m, 2H), 3.46–3.43 (m, 1H), 1.78–1.70 (m, 2H), 1.47(d, J=6.8, 3H), 0.86 (t, J=7.3, 3H).

EXAMPLE 45(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 146, Structure 13 of Scheme II, where R₃=ethyl, R₂=propyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18 from Compound 111 (Structure 9 of Scheme II, whereR₁=trifluoromethyl) and 4-heptanone. ¹H NMR (500 MHz, CDCl₃) 12.1 (bs,1H), 7.30 (d, J=8.8, 1H), 7.19 (s, 1H), 6.95 (d, J=8.8, 1H), 3.70–3.51(m, 4H), 1.88–1.53 (m, 4H), 1.47–1.36 (m, 2H), 1.05 (t, J=7.3, 3H), 0.70(t, J=7.3, 3H).

EXAMPLE 46(±)-5,6-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 147, Structure 13 of Scheme II, whereR₃=2-ethoxycarbonylethyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 12 and 18. ¹H NMR (500 MHz, CDCl₃) 11.6 (bs, 1H), 7.27 (d,J=8.8, 1H), 7.20 (s, 1H), 6.95 (d, J=8.8, 1H), 4.01 (q, J=7.3, 2H),3.82–3.76 (m, 1H), 3.70–3.58 (m, 2H), 3.56–3.52 (m, 1H), 2.40–2.32 (m,1H), 2.15–2.08 (m, 1H), 2.05–1.98 (m, 1H), 1.70–1.62 (m, 1H), 1.46 (d,J=6.4, 3H), 1.18 (t, J=7.3, 3H).

EXAMPLE 47 6-Ethyl-5-methyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 148, Structure 11 of Scheme II, where R₃=methyl, R₂=ethyl,R₁=H)

This compound was prepared in a similar fashion as that described inExample 12 from structure 9 of Scheme II (where R₁=H) and 3-pentanone asa yellow solid: ¹H NMR (500 MHz, DMSO-d₆) 11.23 (s, 1H), 8.58 (d, J=9.5,1H), 7.56 (d, J=8.6, 1H), 7.14 (d, J=8.6, 1H), 6.69 (d, J=9.5, 1H), 2.76(q, J=7.5, 1H), 2.50 (s, 1H), 2.44 (s, 3H), 1.23 (t, J=7.5, 3H).

EXAMPLE 48(±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 149, Structure 13 of Scheme II, where R₃=methyl, R₂=ethyl,R₁=H, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 18 from Compound 148 (Structure 11 of Scheme II, whereR₃=methyl, R₂=ethyl, R₁=H). ¹H NMR (500 MHz, CDCl₃) 11.16 (s, 1H), 7.75(d, J=9.5, 1H), 6.81 (d, J=8.5, 1H), 6.71 (d, J=9.6, 1H), 3.60–3.45 (m,3H), 3.44–3.31 (m, 1H), 1.89–1.75 (m, 2H), 1.11 (d, J=6.8, 3H), 1.06 (t,J=7.3, 3H).

EXAMPLE 495,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 150, Structure 15 of Scheme II, where R₃=R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

To a solution of Compound 123 (Structure 13 of Scheme II, whereR₃=R₂=methyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl) (0.35 g, 0.97mmol) in 30 mL CH₂Cl₂ was added DDQ (0.35 g, 1.5 mmol, 1.5 eq) in smallportions. The resulting green mixture was stirred at rt for about 60 minuntil almost no more starting material was visible on TLC. Then 5% aq.NaHCO₃ (30 mL) was added and the mixture was extracted with EtOAc (3×50mL) and the combined organic layers were washed with 5% aq. NaHCO₃ (30mL) and brine, dried over MgSO₄ and concentrated. Purification bychromatography (Silica gel, hexane:EtOAc 2:1 to 0:1 gradient) affordedCompound 150 (195 mg, 56%) as a slightly yellow solid: ¹H NMR (500 MHz,CDCl₃) 11.4 (bs, 1H), 7.55 (d, J=8.8, 1H), 7.17 (d, J=8.8, 1H), 7.16 (s,1H), 4.71 (q, J_(H-F)=8.3, 2H), 2.43 (s, 3H), 2.33 (s, 3H).

An alternate oxidation method was also used as described as follow:

To a solution of Compound 123 (10 mg, 0.03 mmol) in 10 mL CH₂Cl₂ wasadded MnO₂ (approx. 0.3 g, 3.5 mmol, 100 eq) in portions until no morestarting material was visible on TLC. Then EtOAc (10 mL) was added andthe suspension was filtered through a short pad of celite. The solidswere rinsed several times with EtOAc and the combined filtrates wereconcentrated. Purification by chromatography (Silica gel, hexane:EtOAc2:1 to 0:1 gradient) afforded Compound 150 as a slightly yellow solid.

EXAMPLE 506-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 151, Structure 15 of Scheme II, where R₃=methyl, R₂=ethyl,R₁=H, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 149 (Structure 13 of Scheme II, whereR₃=methyl, R₂=ethyl, R₁=H, R₄=2,2,2-trifluoroethyl). ¹H NMR (500 MHz,CDCl₃) 11.20 (s, 1H), 8.54 (d, J=9.7, 1H), 7.46 (d, J=8.6, 1H), 7.16 (d,J=8.7, 1H), 6.77 (d, J=9.7, 1H), 4.69 (q, J=8.4, 2H), 2.83 (q, J=7.6,2H), 2.56 (s, 3H), 1.23 (t, J=7.6, 3H).

EXAMPLE 516-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 152, Structure 15 of Scheme II, where R₃=H R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExamples 18 and 49 from Compound 112 (Structure 11 of Scheme II, whereR₃=H, R₂=methyl, R₁=trifluoromethyl). ¹H NMR (500 MHz, CDCl₃) 11.1 (bs,1H), 7.92 (d, J=8.8, 1H), 7.39 (d, J=8.8, 1H), 6.99 (s, 1H), 6.80 (s,1H), 5.18 (q, J_(H-F)=8.8, 1H), 2.58 (s, 3H).

EXAMPLE 526-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 153, Structure 15 of Scheme II, where R₁=methyl, R₂=ethyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 134 (Structure 13 of Scheme II, whereR₃=methyl, R₂=ethyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl). ¹HNMR (500 MHz, CDCl₃) 12.2 (bs, 1H), 7.57 (d, J=8.8, 1H), 7.25 (d, J=8.8,1H), 7.18 (s, 1H), 4.62 (q, J_(H-F)=8.3, 2H), 2.45 (q, J=7.8, 2H), 2.34(d, J=1.9, 3H), 1.24 (t, J=7.8, 3H).

EXAMPLE 535-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 154, Structure 15 of Scheme II, where R₃=ethyl, R₂=methyl,R₁=trifluoromethyl, R₁=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 145 (Structure 13 of Scheme II, where R₃=ethyl,R₂=methyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl). ¹H NMR (500MHz, CDCl₃) 12.6 (bs, 1H), 7.56 (d, J=8.8, 1H), 7.28 (d, J=8.8, 1H),7.17 (s, 1H), 4.70 (q, J_(H-F)=8.3, 2H), 2.89 (q, J=7.3, 2H), 2.46 (s,3H), 1.01 (t, J=7.3, 3H).

EXAMPLE 545-Ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 155, Structure 15 of Scheme II, where R₃=ethyl, R₁=propyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 146 (Structure 13 of Scheme II, where R₃=ethyl,R₂=propyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl). ¹H NMR (500MHz, CDCl₃) 11.7 (bs, 1 H), 7.55 (d, J=8.8, 1H), 7.19 (d, J=8.8, 1H),7.15 (s, 1H), 4.71 (q, J_(H-F)=8.3, 2H), 2.88 (q, J=7.3, 2H), 2.79 (t,J=7.8, 2H), 1.64–1.58 (m, 2H), 1.06 (t, J=7.3, 3H), 0.98 (t, J=7.3, 3H).

EXAMPLE 555,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 156. Structure 15 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₁=trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 119 (Structure 13 of Scheme II, where R₃,R₂=—(CH₂)₃—, R₁=trifluoromethyl, R₄=trifluoroethyl). ¹H NMR (500 MHz,CDCl₃) 11.3 (bs, 1H), 7.57 (d, J=8.8, 1H), 7.21 (d, J=8.8, 1H), 7.20 (s,1H), 4.66 (q, J_(H-F)=8.3, 2H), 3.16–3.14 (m, 2H), 2.93–2.90 (m, 2H),2.53–2.49 (m, 2H).

EXAMPLE 568-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 157, Structure 17 of Scheme II, where R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was isolated as a minor product in the same reaction asthat described in Example 55 from Compound 119 (Structure 13 of SchemeII, where R₃, R₂=—(CH₂)₃—, R₁=trifluoromethyl, R₄=trifluoroethyl). ¹HNMR (500 MHz, CDCl₃) 12.2 (bs, 1H), 7.58 (d, J=9.3, 1H), 7.48 (d, J=9.3,1H), 7.30 (s, 1H), 5.16 (s, 1H), 4.67–4.63 (m, 1H), 4.63 (s, 1H),4.21–4.16 (m, 1H), 2.77 (d, J=11.2, 1H), 2.65 (d, J=10.7, 1H).

EXAMPLE 579-Trifluoroethyl-4-trifluoromethyl-9H-benzo[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 158, Structure 15 of Scheme II, where R₃, R₂=—(CH═CH)₂—,R₁=trifluoromethyl, R₄=trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 132 (Structure 13 of Scheme II, where R₃,R₂=—(CH₂)₄—, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl). ¹H NMR (500MHz, CDCl₃) 11.4 (bs, 1H), 8.39 (d, J=8.8, 1H), 8.19 (d, J=8.8, 1H),7.82 (d, J=8.3, 1H), 7.76 (d, J=9.3, 1H), 7.57 (t, J=7.3, 1H), 7.34 (t,J=8.3, 1H), 7.21 (s, 1H), 5.46 (q, J_(H-F)=8.3, 2H).

EXAMPLE 586-Trifluoroethyl-4-trifluoromethyl-6,7,8,9-tetrahydrocyclopetano[i]pyrrolo[2,3-f]quinolin-2(1H)-one(Compound 159, Structure 16 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=trifluoroethyl)

This compound was isolated as a regioisomer of Compound 156 in Example49. ¹H NMR (500 MHz, CDCl₃) 10.8 (bs, 1H), 7.84 (s, 1H), 7.47 (s, 1H),6.81 (s, 1H), 5.13 (q, J_(H-F)=9.3, 1H), 3.06–3.00 (m, 2H), 2.62–2.56(m, 2H).

EXAMPLE 595-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 160, Structure 15 of Scheme II, whereR₃=3-trifluoromethylphenyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 139 (Structure 13 of Scheme II, whereR₃=3-trifluoromethylphenyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl). ¹H NMR (500 MHz, CDCl₃) 12.8 (bs, 1H), 7.65(d, J=8.8, 1H), 7.60 (d, J=8.3, 1H), 7.53 (dd, J=8.3, 8.3, 1H), 7.46 (s,1H), 7.45 (d, J=8.3, 1H), 7.39 (d, J=8.8, 1H), 7.00 (s, 1H), 4.78 (q,J_(H-F)=8.3, 2H), 2.33 (s, 3H).

EXAMPLE 605-(4-Fluorophenyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 161, Structure 15 of Scheme II, where R₁=4-fluorophenyl,R₂=methyl, R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 140 (Structure 13 of Scheme II, whereR₃=4-fluorophenyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl). ¹H NMR (500 MHz, CDCl₃) 11.1 (bs, 1H), 7.98(d, J=8.8, 1H), 7.40 (d, J=8.8, 1H), 7.29 (dd, J=8.8, 5.4, 1H), 7.16(dd, J=8.8, 8.3, 1H), 6.76 (s, 1H), 5.26 (q, J_(H-F)=8.8, 2H), 2.38 (s,3H).

EXAMPLE 615-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 162, Structure 15 of Scheme II, whereR₃=2-ethoxycarbonylethyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 49 from Compound 147 (Structure 13 of Scheme II, whereR₃=2-ethoxycarbonylethyl, R₂=methyl, R₁=trifluoromethyl,R₄=2,2,2-trifluoroethyl). ¹H NMR (500 MHz, CDCl₃) 11.7 (bs, 1H), 7.55(d, J=8.3, 1H), 7.21 (d, J=8.8, 1H), 7.17 (s, 1H), 4.71 (q, J_(H-F)=7.8,2H), 3.94 (q, J=7.3, 2H), 3.24 (t, J=7.3, 2H), 2.49 (s, 3H), 2.38 (t,J=7.3, 3H), 1.07 (t, J=7.3, 3H).

EXAMPLE 627-Ethyl-8-methyl-6-(2,2,2-trifluoroethyl)-4-trifluoromethyl-6H-pyrrolo[2,3-g]quinolin-2(1H)-one(Compound 163, Structure 16 of Scheme II, where R₃=ethyl, R₂=methyl,R₁=trifluoromethyl, R₄=2,2,2-trifluoroethyl)

This compound was a regioisomer of Compound 153 and prepared in asimilar fashion as that described in Example 52. ¹H NMR (500 MHz, CDCl₃)9.4 (bs, 1H), 7.68 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 4.69 (q,J_(H-F)=8.3, 2H), 2.85 (q, J=7.8, 2H), 2.30 (s, 3H), 1.25 (t, J=7.8,3H).

EXAMPLE 635-Hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 164, Structure 19 of Scheme III, where R₃=hydroxymethyl,R₄=ethyl, R₅=2,2,2-trifluoroethyl)

This compound was prepared by the general oxidation procedure describedin Example 49 from Compound 153 (Structure 18 of Scheme III, whereR₂=ethyl). ¹H NMR (500 MHz, CDCl₃) 12.4 (bs, 1H), 7.84 (d, J=8.8, 1H),7.24 (d, J=8.8, 1H), 7.02 (s, 1H), 5.10 (q, J_(H-F)=8.8, 2H), 4.92 (s,2H), 4.85 (bs, 1H), 3.00 (q, J=7.3, 2H), 1.29 (t, J=7.3, 3H).

EXAMPLE 645-Methyl-6-(1-hydroxyethyl)-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 165, Structure 19 of Scheme III, where R₃=methyl,R₄=1-hydroxyethyl, R₅=2,2,2-trifluoroethyl)

This compound was prepared by the general oxidation procedure describedin Example 49 from Compound 153 (Structure 18 of Scheme III, whereR₂=ethyl). ¹H NMR (500 MHz, CDCl₃) 11.2 (bs, 1H), 7.89 (d, J=8.8, 1H),7.33 (d, J=8.8, 1H), 6.96 (s, 1H), 5.63–5.54 (m, 1H), 5.49–5.44 (m, 1H),5.37–5.28 (m, 1H), 4.81–4.77 (m, 1H), 2.37 (d, J=2.4, 3H), 1.62 (d,J=6.8, 3H).

EXAMPLE 655-Methyl-6-acetyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 166, Structure 19 of Scheme III, where R₃=methyl, R₁=acetyl,R₅=2,2,2-trifluoroethyl)

This compound was isolated as an over oxidized product in Example 64. ¹HNMR (500 MHz, CDCl₃) 10.5 (bs, 1H), 7.64 (d, J=8.8, 1H), 7.31 (s, 1H),7.20 (d, J=8.8, 1H), 5.39 (q, J_(H-F)=7.8, 2H), 2.72 (s, 3H), 2.64 (s,3H).

EXAMPLE 665-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 167, Structure 19 of Scheme III, where R₃=formyl, R₄=methyl,R₅=2,2,2-trifluoroethyl)

This compound was prepared by the general oxidation procedure describedin Example 49 from Compound 150 (Structure 18 of Scheme III, whereR₁=R₂=methyl). ¹H NMR (500 MHz, CDCl₃) 11.9 (bs, 1H), 10.16 (d, J=1.5,1H), 8.04 (d, J=8.8, 1H), 7.49 (d, J=8.8, 1H), 7.00 (s, 1H), 5.37 (q,J_(H-F)=8.8, 2H), 2.85 (s, 3H).

EXAMPLE 675-Acetyloxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 168, Structure 20 of Scheme III)

In a 50 mL r.b. flask, a solution of 30 mg (0.08 mmol) of Compound 164(Structure 19 of Scheme III, where R₃=hydroxymethyl, R₄=ethyl,R₅=2,2,2-trifluoroethyl) in 10 mL THF was treated with triethylamine(0.5 mL, 3.5 mmol, 40 eq) followed by acetic anhydride (0.2 mL, 2 mmol,25 eq) and DMAP (1 mg, 0.008 mmol, 0.1 eq). The mixture was stirred atrt for 2 h and then 30 mL 2N HCl and 20 mL EtOAc added and vigorouslystirred for 1 h. The layers were separated and the water layer wasextracted with EtOAc (20 mL). The combined organic layers were washedwith 20 mL portions of 2N HCl, water, 2N NaOH and brine and dried overMgSO₄. Concentration followed by purification by flash chromatography(hexane: EtOAc 5:1 to 0:1 gradient) afforded Compound 168. ¹H NMR (500MHz, CDCl₃) 11.1 (bs, 1H), 7.54 (d, J=8.8, 1H), 7.25 (d, J=8.8, 1H),7.13 (s, 1H), 4.73 (q, J_(H-F)=8.3, 2H), 4.68 (s, 2H), 3.26 (s, 3H),2.92 (q, J=7.3, 2H), 1.27 (t, J=7.3, 3H).

EXAMPLE 682-Acetyloxy-5-hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinoline(Compound 169, Structure 23 of Scheme III)

This compound was prepared by treatment of Compound 164 (Structure 19 ofScheme III, where R₃=hydroxymethyl, R₄=ethyl, R₅=2,2,2-trifluoroethyl)with acetic anhydride in Example 67. ¹H NMR (500 MHz, CDCl₃) 7.79 (s, 2H), 7.57 (s, 1H), 4.98 (s, 2H), 4.82 (q, J_(H-F)=8.3, 2H), 3.03 (q,J=7.8, 2H), 2.43 (s, 3H), 1.33 (t, J=7.8, 3H).

EXAMPLE 696-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 170, Structure 21 of Scheme III)

This compound was isolated as a by-product in the treatment of Compound164 (Structure 19 of Scheme III, where R₃=hydroxymethyl, R₄=ethyl,R₅=2,2,2-trifluoroethyl) with acetic anhydride in Example 67. ¹H NMR(500 MHz, CDCl₃) 11.2 (bs, 1H), 7.94 (d, J=8.8, 1H), 7.39 (d, J=8.8,1H), 7.00 (s, 1H), 6.82 (d, J=2.0, 1H), 5.19 (q, J_(H-F)=8.8, 2H), 2.94(q, J=7.3, 2H), 1.42 (t, J=7.3, 3H).

EXAMPLE 705-Ethoxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 171, Structure 20 of Scheme III)

This compound was isolated as a by-product in the treatment of Compound164 (Structure 19 of Scheme III, where R₃=hydroxymethyl, R₄=ethyl,R₅=2,2,2-trifluoroethyl) with acetic anhydride in Example 67. ¹H NMR(500 MHz, CDCl₃) 11.3 (bs, 1H), 7.92 (d, J=8.8, 1H), 7.34 (d, J=8.8,1H), 6.95 (s, 1H), 5.22 (q, J_(H-F)=8.8, 2H), 4.72 (s, 2H), 3.37 (q,J=6.8, 2H), 3.00 (q, J=7.3, 2H), 1.29 (t, J=7.3, 3H), 1.07 (t, J=6.8,3H).

EXAMPLE 716-(1-Methoxyethyl)-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 172, Structure 22 of Scheme III)

In a 50 mL r.b. flask, a solution of 5 mg (0.01 mmol) of Compound 165(Structure 19 of Scheme III, where R₃=methyl, R₄=1-hydroxyethyl,R₅=2,2,2-trifluoroethyl) in 5 mL MeOH was treated with aqueous 2.5 N HCl(2 mL, 5 mmol). The mixture was stirred at rt for 20 h and then 30 mLwater was added and the water layer was extracted with EtOAc (2×30 mL).The combined organic layers were washed with brine and dried over MgSO₄.Concentration followed by purification by flash chromatography(hexane:EtOAc 2:1 to 1:1 gradient) afforded 4.2 mg of Compound 172 as aslightly yellow solid. ¹H NMR (500 MHz, CDCl₃) 13.2 (bs, 1H), 7.64 (d,J=8.8, 1H), 7.39 (d, J=8.8, 1H), 7.20 (s, 1H), 5.27–5.20 (m, 1H),4.69–4.85 (m, 2H), 3.25 (s, 3H), 2.37 (d, J=1.8, 3H), 1.63 (d, J=7.0,3H).

EXAMPLE 727-Allyl-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one(Compound 173, Structure 26 of Scheme IV, where R₂=methyl, R₃=allyl)

In a 250 mL r.b. flask a suspension of5-amino-4-trifluoromethylquinolin-2-one (Structure 24 of Scheme IV) (42mg, 0.18 mmol) in 4 mL conc. HCl was cooled to −1° C. and a solution ofNaNO₂ (20 mg, 0.6 mmol) in water (0.5 mL) was added dropwise in 1 min.The dark brown suspension was stirred at −1° C. for 1 h and then asolution of SnCl₂.2H₂O (0.20 g, 0.6 mmol) in conc. HCl (1 mL) was addeddropwise in 1 min. The light yellow suspension of Compound 174(Structure 25 of Scheme IV) was stirred at −1° C. for 30 min and thenkept in a refrigerator at −1° C. for 3 days. To the crude suspension ofthe hydrazine was added a solution of 5-hexen-2-one (0.1 mL, 0.9 mmol, 5eq) in 5 mL of EtOH and the mixture was refluxed for 3 h. Then themixture was diluted with 30 mL of water and extracted with EtOAc (2×30mL) and the combined organic layers were washed with brine, dried overMgSO₄ and concentrated. Purification by chromatography (Silica gel,hex:EtOAc 3:1) afforded Compound 173 as a yellow solid. ¹H NMR (500 MHz,CDCl₃) 11.1 (bs, 1H), 9.3 (bs, 1H), 7.80 (d, J=8.3, 1H), 7.26 (d, J=8.3,1H), 6.95 (s, 1H), 6.02–5.95 (m, 1H), 5.05 (dd, J=17.1, 2.0, 1H), 4.97(dd, J=9.8, 2.0, 1H), 3.50 (d, J=6.3, 1H), 2.46 (s, 3H).

EXAMPLE 736-Ethyl-7-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one(Compound 175, Structure 26 of Scheme IV, where R₂=ethyl, R₃=methyl)

This compound was prepared in a similar fashion as that described inExample 72 from Compound 174 (Structure 25 of Scheme IV) and3-pentanone. ¹H NMR (500 MHz, CDCl₃) 11.2 (bs, 1H), 9.1 (bs, 1H), 7.79(d, J=8.3, 1H), 7.27 (d, J=8.8, 1H), 6.96 (s, 1H), 2.87 (q, J=7.8, 2H),2.27 (s, 1H), 1.27 (t, J=7.8, 3H).

EXAMPLE 747-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one(Compound 176, Structure 26 of Scheme IV, where R₂=methyl,R₃=3-trifluoromethylphenyl)

This compound was prepared in a similar fashion as that described inExample 72 from Compound 174 (Structure 25 of Scheme IV) and3-trifluorophenylacetone. ¹H NMR (500 MHz, CDCl₃) 12.9 (bs, 1H), 8.9(bs, 1H), 7.90 (d, J=8.8, 1H), 7.71 (s, 1H), 7.64 (s, 3H), 7.30 (d,J=8.8, 1H), 7.29 (s, 1H), 2.59(s, 3H).

EXAMPLE 757-(2-Hydroxyethyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one(Compound 177, Structure 26 of Scheme IV, where R₂=methyl.R₃=2-hydroxyethyl

This compound was prepared in a similar fashion as that described inExample 72 from Compound 174 (Structure 25 of Scheme IV) and5-hydroxy-2-pentanone. ¹H NMR (500 MHz, CDCl₃) 11.3 (bs, 1H), 9.4 (bs,1H), 7.89 (d, J=8.5, 1H), 7.29 (d, J=8.5, 1H), 6.97 (d, J=0.6, 1H), 3.78(t, J=7.3, 2H), 3.23 (t, J=7.3, 2H), 2.51 (s, 3H).

EXAMPLE 76(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 178, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=trifluoroethyl) and(−)-4c,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 179, Structure 13 of Scheme II, where R₃, R₂=—(CH₂)₃—,R₁=trifluoromethyl, R₄=trifluoroethyl)

Compounds 178 and 179 were enantiomers of Compound 119 and separated bychiral HPLC.

EXAMPLE 774-Trifluoromethyl-6,7-dihydro-7,7,9-trimethyl-pyrido[2,3-g]quinolin-2(1H)-one(Compound 180, Structure 28 of Scheme V, where R₁=trifluoromethyl)

A mixture of Compound 181 (Structure 8 of Scheme V, whereR₁=trifluoromethyl), iodine and acetone in a sealed tube was heated at135° C. overnight and the mixture was concentrated. Chromatography ofthe crude mixture afforded Compound 180 as a yellow solid. ¹H NMR (500MHz, CDCl₃) 7.21 (s, 1H), 6.83 (m, 1H), 6.77 (s, 1H), 5.68 (s, 1H), 5.46(bs, 1H), 2.02 (s, 3H) and 1.31 (s, 6H).

EXAMPLE 788-(2,2,2-Trifluoroethyl)-5,6,7,8-tetrahydro-5,7,7-trimethylpyrido[3,2-f]quinolin-2(1H)-one(Compound 182, Structure 29 of Scheme V, where R₁=H)

A mixture of Compound 183 (Structure 8 of Scheme V, where R₁=H), iodineand acetone in a sealed tube was heated at 135° C. overnight and themixture was concentrated. Chromatography of the crude mixture affordedCompound 184 (Structure 27 of Scheme V, where R₁=H) as a yellow solid.

Compound 184 was treated with TFA and NaBH₄ in a similar fashion as thatdescribed in Example 18 to afford Compound 182 as a yellow solid. ¹H NMR(400 MHz, CDCl₃) 11.29 (s, 1H), 7.96 (d, J=9.9, 1H), 7.15 (d, J=9.1,1H), 7.06 (d, J=9.1, 1H), 6.69 (d, J=9.8, 1H), 3.84 (q, J=8.7, 2H),3.41–3.47 (m, 1H), 2.08 (dd, J=13.6, 7.3, 1H), 1.88 (dd, J=13.6, 7.3,1H), 1.39 (s, 3H), 1.35 (d, J=6.7, 3H), 1.08 (s, 3H).

EXAMPLE 79 4,5,7-Tri(trifluoromethyl)pyrido[3,2-f]quinolin-2(1H)-one(Compound 185, Structure 30 of Scheme V, where R₁=trifluoromethyl)

A mixture of Compound 181 and 1,1,1,5,5,5-hexafluoro-2,4-pentadiene washeated to 170° C. for 2 h and was poured into ice-water. The crudemixture was extracted with EtOAc and the combined organic phase wasconcentrated. Chromatography provided Compound 185 as a white solid. ¹HNMR (400 MHz, acetone-d₆) 11.15 (s, 1H), 8.25 (s, 1H), 8.04 (d, J=9.0,1H), 7.58 (d, J=9.0, 1H), 6.99 (s, 1H).

EXAMPLE 80 5,7-Bis(trifluoromethyl)pyrido[3,2-f]quinolin-2(1H)-one(Compound 186, Structure 30 of Scheme V, where R₁=H)

This compound was prepared in a similar fashion as that described inExample 79 from Compound 183 (Structure 8 of Scheme V, where R₁=H) as awhite solid. ¹H NMR (400 MHz, CDCl₃) 12.49 (s, 1H), 8.60 (d, J=9.9, 1H),8.28 (d, J=9.4, 1H), 8.19 (s, 1H), 7.99 (d, J=9.4, 1H), 6.79 (d, J=9.9,1H).

EXAMPLE 814-Trifluoromethyl-7-methyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 187, Structure 33 of Scheme VI, where R₁=methyl, n=1)

Preparation of 1-acetyl-2-methyl-6-nitrotetrahydroquinoline (Compound188, Structure 32 of Scheme VI, where R₁=methyl, n=1)

In a 100-mL r.b. flask, a solution of Compound 189 (Structure 31 ofScheme VI, where R₁=methyl, n=1) (1.56 g, 8.2 mmol) in1,2-dichloroethane (15 mL) was treated with Yb(OTf)₃ (0.622 g, 1.0 mmol,12 mol %) and fuming nitric acid (2.0 mL, 47.0 mmol, 5.7 equiv). Thereaction mixture was stirred at rt for 16 h. The reaction mixture wasdiluted with CH₂Cl₂ (50 mL), washed with H₂O (50 mL) and brine (50 mL).Dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (SiO₂, 4×20 cm, 25% EtOAc/hexaneas eluent) to afford 1.22 g (63%) of Compound 188 as white solid. R_(f)0.45 (SiO₂.50% EtOAc/hexane). ¹H NMR (400 MHz, CDCl₃) 8.10–8.00 (m, 2H),7.44 (d, 1H, J=8.5), 4.76 (sixtet, 1H, J=6.6), 2.85–2.79 (m, 1H),2.74–2.68 (m, 1H), 2.38–2.30 (m, 1H), 2.24 (s, 3H), 1.58–1.54 (m, 1H),1.18 (d, 3H, J=6.6).

4-Trifluoromethyl-7-methyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 187, Structure 33 of Scheme VI, where R₁=methyl, n=1)

In a 100-mL r.b. flask, a solution of Compound 188 (1.22 g, 5.2 mmol) ina 1:1 mixture of CH₂Cl₂/EtOH (30 mL) was treated with 10% Pd/C (140 mg,11 wt % equiv). The reaction mixture was stirred under hydrogen (1 atm)at rt for 18 h. The reaction mixture was filtered through a pad ofcelite and rinsed with CH₂Cl₂ (100 mL). The filtrate was concentrated togive 1.02 g (96%) of the corresponding amine which was used immediatelyin the next reaction without further purification.

In a 100-mL r.b. flask, a solution of the amine (1.02 g, 5.0 mmol) in a95:5 mixture of toluene/water (30 mL) was heated to reflux for 16 h.After cooling to rt, the reaction mixture was dried (MgSO₄), filteredand concentrated in vacuo. The residue was then dissolved in 20 mL conc.H₂SO₄ and heated to 95° C. for 4 h. The reaction mixture was cooled tort and poured onto 200 mL of ice-water, neutralized with 6N NaOH to pH 7and extracted with EtOAc (3×250 mL). The combined extracts were washedwith brine (2×200 mL), dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash column chromatography (SiO₂,3×20 cm, 50–70% EtOAc in hexane gradient eluent) to afford 0.21 g (15%)of Compound 187 as a yellow solid. R_(f) 0.30 (SiO₂, 2:1=EtOAc:hexane).¹H NMR (400 MHz, CDCl₃) 11.70 (s, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.80(s, 1H), 4.02 (br, s, 1H), 3.48–3.43 (m, 1H), 2.95–2.91 (m, 2H),2.01–1.96 (m, 1H), 1.25 (d, 3H, J=6.1), 0.89–0.85 (m, 1H).

EXAMPLE 824-Trifluoromethyl-7,8-dihydro-6H-pyrrolo[2,3-g]quinolin-2(1H)-one(Compound 190, Structure 33 of Scheme VI, where R₁=H, n=0)

This compound was prepared in a similar fashion as that described inExample 81 from Compound 191 (Structure 31 of Scheme VI, where R₁=H,n=0). ¹H NMR (acetone-d₆) 7.28 (s, 1H), 6.82 (s, 2H), 5.25 (bs, 1H),3.60 (t, J=8.2, 2H), 3.12 (t, J=8.2, 2H).

EXAMPLE 834-Trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 192, Structure 33 of Scheme VI, where R₁=H, n=1)

This compound was prepared in a similar fashion as that described inExample 81 from Compound 193 (Structure 31 of Scheme VI, where R₁=H,n=1). ¹H NMR (400 MHz, CDCl₃) 11.18 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H),6.80 (s, 1H), 4.08 (s, 1H), 3.35 (t, 2H, J=5.4), 2.91 (t, 2H, J=6.4),1.97 (m, 2H).

EXAMPLE 844-Trifluoromethyl-7-methyl-6-propyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 194, Structure 34 of Scheme VI, where R₁=methyl, R₂=propyl,n=1)

In a 25-mL r.b. flask, a solution of Compound 187 (Structure 33 ofScheme VI, where R₁=methyl, n=1) (12.2 mg, 0.043 mmol) in MeOH (5 mL)was treated with propionaldehyde (2 mL), AcOH (2 mL) and NaCNBH₃. Thereaction mixture was stirred at rt for 18 h. The reaction mixture waspoured onto ice-water (50 mL), neutralized with NaHCO₃ to pH 7 andextracted with EtOAc (3×50 mL). The combined extracts were washed withH₂O (50 mL) and brine (50 mL), dried (MgSO₄), filtered and concentratedin vacuo. The residue was purified by flash column chromatography (SiO₂,50% EtOAc/hexane as eluent) to afford 5.0 mg (34%) of Compound 194 as ayellow solid. R_(f) 0.51 (SiO₂, 2:1=EtOAc:hexane). ¹H NMR (400 MHz,CDCl₃) 11.45 (br. s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 6.75 (s, 1H), 3.55(m, 1H), 3.35–3.29 (m, 1H), 3.21–3.12 (m, 1H), 2.95–2.80 (m, 2H),2.00–1.78 (m, 2H), 1.72–1.60 (m, 1H), 1.17 (d, 3H, J=6.5), 0.97 (t, 3H,J=7.3), 0.89–0.85 (m, 1H).

EXAMPLE 854-Trifluoromethyl-7-methyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 195, Structure 34 of Scheme VI, where R₁=methyl,R₂=cyclopropylmethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 187 (Structure 33 of Scheme VI, whereR₁=methyl, n=1) and cyclopropanecarboxaldehyde. ¹H NMR (400 MHz, CDCl₃)10.91 (br. s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 6.94 (s, 1H), 3.65 (m,1H), 3.35 (dd, 1H, J=15.0, 5.5), 3.09 (dd, 1H, J=15.0, 6.2), 2.97–2.82(m, 2H), 2.00–1.94 (m, 1H), 1.84–1.79 (m, 1H), 1.17 (d, 3H, J=6.5),0.88–0.85 (m, 1H), 0.58 (m, 2H), 0.28 (dd, 2H, J=10.3, 5.0).

EXAMPLE 864-Trifluoromethyl-7-methyl-6-ethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 196, Structure 34 of Scheme VI, where R₁=methyl, R₂=ethyl,n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 187 (Structure 33 of Scheme VI, whereR₁=methyl, n=1) and acetaldehyde. ¹H NMR (400 MHz, CDCl₃) 11.19 (br. s,1H), 7.11 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 3.55 (m, 1H), 3.47–3.32(m, 2H), 2.93–2.80 (m, 2H), 1.93–1.79 (m, 2H), 1.22 (t, 3H, J=7.0), 1.18(d, 3H, J=6.4).

EXAMPLE 874-Trifluoromethyl-7-methyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 197, Structure 34 of Scheme VI, where R₁=methyl,R₂=2,2,2-trifluoroethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 187 (Structure 33 of Scheme VI, whereR₁=methyl, n=1) and trifluoroacetaldehyde ethyl hemiacetal. ¹H NMR (400MHz, CDCl₃) 11.08 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H),3.99 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.10–2.95 (m, 1H), 2.92–2.82(m, 1H), 2.07–1.97 (m, 1H), 1.93–1.80 (m, 1H), 1.19 (d, 3H, J=6.5).

EXAMPLE 884-Trifluoromethyl-6-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 198, Structure 34 of Scheme VI, where R₁=H,R₂=2,2,2-trifluoroethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 192 (Structure 33 of Scheme VI, where R₁=H,n=1) and trifluoroacetaldehyde ethyl hemiacetal. ¹H NMR (400 MHz, CDCl₃)11.32 (br. s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 3.88 (q,2H, J=8.9), 3.47 (t, 2H, J=5.6), 2.93 (t, 2H, J=6.3), 2.03 (m, 2H).

EXAMPLE 894-Trifluoromethyl-6-propyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 199, Structure 34 of Scheme VI, where R₁=H, R₂=propyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 192 (Structure 33 of Scheme VI, where R₁=H,n=1) and propionaldehyde. ¹H NMR (400 MHz, CDCl₃) 11.23 (br. s, 1H),7.07 (s, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 3.34 (t, 2H, J=5.6), 3.26 (t,2H, J=7.4), 2.88 (t, 2H, J=6.3), 1.97 (m, 2H), 1.65 (m, 2H), 0.97 (t,3H, J=7.4).

EXAMPLE 904-Trifluoromethyl-6-ethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 200, Structure 34 of Scheme VI, where R₁=H, R₂=ethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 192 (Structure 33 of Scheme VI, where R₁=H,n=1) and acetaldehyde. ¹H NMR (400 MHz, CDCl₃) 11.23 (br. s, 1H), 7.07(s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 3.39 (q, 2H, J=7.1), 3.31 (t, 2H,J=5.6), 2.88 (t, 2H, J=6.4), 1.98 (m, 2H), 1.18 (t, 3H, J=7.1).

EXAMPLE 914-Trifluoromethyl-6-cyclopropylmethyl-6,7,8,9-tetrahydropyrido[2,3-g]quinolin-2(1H)-one(Compound 201, Structure 34 of Scheme VI, where R₁=H,R₂=cyclopropylmethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 84 from Compound 192 (Structure 33 of Scheme VI, where R₁=H,n=1) and cyclopropanecarboxaldehyde. ¹H NMR (400 MHz, CDCl₃) 11.44 (br.s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J=5.6),3.21 (d, 2H, J=6.2), 2.90 (t, 2H, J=6.3), 1.99 (m, 2H), 1.07 (m, 1H),0.58 (m, 2H), 0.27 (m, 2H).

EXAMPLE 926,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 202, Structure 39 of Scheme VII, where R₁=R₃=R₅=H, R₂=methyl,R₄=trifluoromethyl)

General Method A: Substitution of a propargyl alcohol with a phenol. Toa solution of the propargyl alcohol (1.16 equiv) and DBU(1,8-diazabicyclo[5.4.0]undec-7-ene, 1.3 equiv) in CH₃CN (0.5 mL/mmol)stirred at −5° C. was added trifluoroacetic anhydride (1.16 equiv) andthe flask was stirred for 40 min. In a second flask, to a mixture of thephenol (1.0 equiv) and CuCl (0.01 equiv) in CH₃CN (0.8 mL/mmol) wasadded DBU (1.5 equiv) at 0° C. This solution was added via cannula tothe first flask. The mixture was stirred at 0° C. for 4 h, then allowedto warn to rt. The mixture was partitioned between EtOAc (10 mL/mmol)and water (5 mL/mmol) and the aqueous layer was extracted with EtOAc.The combined organic layers were washed sequentially with 1 N NaHSO₄ (5mL/mmol), NaHCO₃ (5 mL/mmol) and brine (5 mL/mmol), dried over MgSO₄,filtered and concentrated. Flash chromatography affords the desiredproduct as an oil.

1-Nitro-3-(1,1-dimethylprop-2-ynloxy)benzene (Compound 203, Structure 36of Scheme VII, where R₁=R₃=H, R₂=methyl).

This compound was prepared by the above General Method A from2-methyl-3-butyn-2-ol (0.976 g, 11.6 mmol) and 3-nitrophenol (1.39 g,10.0 mmol) in 40% yield (0.76 g) after flash chromatography(hexanes:EtOAc 9:1). ¹H NMR (400 MHz, CDCl₃) 8.11 (t, J=2.2, 1H),7.86–7.96 (m, 1H), 7.48–7.55 (m, 1H), 7.43 (t, J=8.1, 1H), 2.66 (s, 1H),1.70 (s, 6H).

General Method B: Thermal cyclization of a propargyl phenyl ether to a2H-chromene. A solution of the propargyl phenyl ether was heated inN,N-diethylaniline (1–2 M) at 195° C. or reflux for 12–30 h, whereuponthe dark brown solution was partitioned between EtOAc (10 mL/mmol) and1N NaHSO₄ (5 mL/mmol). The aqueous layer was extracted with EtOAc (10mL/mmol) and the combined organic layers were washed sequentially with1N NaHSO₄ (10 mL/mmol) and brine (10 mL/mmol), dried over MgSO₄,filtered and concentrated. Flash chromatography (EtOAc:hexanes) affordedthe desired product.

2,2-Dimethyl-7-nitro-2H-chromene (Compound 204, Structure 37 of SchemeVII, where R₁=R₃=H, R₂=methyl).

This compound was prepared by the above General Method B from Compound203 (0.703 g, 3.71 mmol) in 1.9 mL N,N-diethylaniline heated at 195° C.for 14 h in 18% yield (130 mg) after flash chromatography (hexanes:EtOAc9:1). ¹H NMR (400 MHz, CDCl₃) 7.71 (dd, J=8.3, 2.2, 1H), 7.61 (d, J=2.1,1H), 7.07 (d, J=8.3, 1H), 6.37 (d, J=9.9, 1H), 5.82 (d, J=9.9, 1H), 1.47(s, 6H).

7-Amino-2,2-dimethyl-2H-chroman (Compound 205, Structure 38 of SchemeVII, where R₁=R₃=H, R₂=methyl).

A suspension of Compound 204 (124 mg, 0.655 mmol) and 10% Pd—C (6.2 mg,5 wt %) in 1.3 mL EtOAc and 1.3 mL EtOH was stirred under an atmosphereof hydrogen for 16 h, whereupon the mixture was filtered through Celiteand concentrated. Flash chromatography (hexanes:EtOAc 3:1) afforded 112mg (97%) of Compound 205. ¹H NMR (400 MHz, CDCl₃) δ 6.83 (d, J=8.0, 1H),6.21 (dd, J=8.0, 2.3, 1H), 6.14 (d, J=2.2, 1H), 3.50 (v. broad s, 2H),2.66 (t, J=6.7, 2H), 1.76 (t, J=6.7, 2H), 1.31 (s, 3H).

6,7-Dihydro-8,8-dimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 202, Structure 39 of Scheme VII, where R₁=R₃=R₅=H, R₂=methyl,R₄=trifluoromethyl).

A solution of Compound 205 (9 mg, 0.050 mmol) and4,4,4-trifluoroacetoacetate (57 mg, 0.30 mmol) was heated at 190° C. ina sealed tube for 20 h, whereupon the mixture was cooled andprecipitated with hexanes. Flash chromatography (CH₂Cl₂:MeOH 92:8)afforded 4 mg of a brown solid. Final purification by HPLC (ODSsemi-prep column, MeOH:water 7:3, 3 mL/min) afforded 1.1 mg (7%) ofCompound 205, a white film. ¹H NMR (400 MHz, acetone-d₆) 10.9 (broad s,1H), 7.50 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 2.93 (t, J=6.8, 2H), 1.91(t, J=6.8, 2H), 1.38 (s, 6H).

EXAMPLE 936,7-Dihydro-8,8,10-trimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 206, Structure 39 of Scheme VII, where R₁=R₂=methyl, R₃=R₅=H,R₄=trifluoromethyl)

1-Nitro-2-methyl-3-(1,1-dimethylprop-2-ynloxy)benzene (Compound 207,Structure 36 of Scheme VII, where R₁=R₂=methyl, R₃=H)

This compound was prepared by General Method A (EXAMPLE 92) from2-methyl-3-butyn-2-ol (0.976 g, 11.6 mmol) and 2-methyl-3-nitrophenol(1.53 g, 10.0 mmol) in 61% (1.34 g) yield after flash chromatography(hexanes:EtOAc 11:1). ¹H NMR (400 MHz, CDCl₃) 7.72 (d, J=7.9, 1H), 7.49(d, J=7.8, 1H), 7.22 (t, J=8.0, 1H), 2.60 (s, 1H), 2.36 (s, 3H), 1.69(s, 6H).

2,2,8-Trimethyl-7-nitro-2H-chromene (Compound 208, Structure 37 ofScheme VII, where R₁=R₂=methyl, R₃=H).

This compound was prepared by General Method B (EXAMPLE 92) fromCompound 207 (0.415 g, 1.89 mmol) in 2 mL N,N-diethylaniline heated at190° C. for 16 h in 59% yield (59%) after flash chromatography(hexanes:EtOAc 9:1). ¹H NMR (400 MHz, CDCl₃) 7.39 (d, J=8.2, 1H), 6.91(d, J=8.2, 1H), 6.33 (d, J=9.8, 1H), 5.78 (d, J=9.8, 1H), 2.36 (s, 3H),1.46 (s, 6H).

7-Amino-2,2,8-trimethyl-2H-chroman (Compound 209, Structure 38 of SchemeVII, where R₁=R₂=methyl, R₃=H).

A suspension of Compound 208 (241 mg, 1.10 mmol) and 10% Pd—C (12 mg, 5wt %) in 2.2 mL EtOAc and 2.2 mL EtOH was stirred under an atmosphere ofhydrogen for 16 h, whereupon the mixture was filtered through Celite andconcentrated. Flash chromatography (hexanes:EtOAc 3:1) afforded 210 mg(100%) of Compound 209. ¹H NMR (400 MHz, CDCl₃) 6.72 (d, J=8.0, 1H),6.24 (d, J=8.0, 1H), 3.48 (broad s, 2H), 2.68 (t, J=6.8, 2H), 2.01 (s,3H), 1.74 (t, J=6.8, 2H), 1.31 (s, 6H).

6,7-Dihydro-8,8,10-trimethyl-4-(trifluoromethyl)-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 206, Structure 39 of Scheme VII, where R₁=R₂=methyl, R₃=R₅=H,R₄=trifluoromethyl).

A solution of Compound 209 (39 mg, 0.21 mmol) and4,4,4-trifluoroacetoacetate (195 mg, 1.03 mmol) in 0.5 mL diphenyl etherwas heated at 190° C. in a sealed tube for 44 h, whereupon the mixturewas cooled and precipitated with hexanes and filtered. Flashchromatography (CH₂Cl₂:ether) afforded 6.5 mg (10%) of Compound 209 as awhite solid. ¹H NMR (400 MHz, CDCl₃) 9.07 (broad s, 1H), 7.40 (s, 1H),6.82 (s, 1H), 2.89 (t, J=6.7, 2H), 2.26 (s, 3H), 1.86 (t, J=6.7, 2H),1.39 (s, 6H).

EXAMPLE 94(±)-6,7-Dihydro-6-ethyl-4-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 210, Structure 39 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=methyl)

1-Nitro-3-(pent-2-ynyloxy)benzene (Compound 211, Structure 36 of SchemeVII, where R₁=R₂=H, R₃=ethyl).

To a solution of 3-nitrophenol (7.5 g, 54 mmol) and K₂CO₃ (10.4 g, 75.6mmol) in 27 mL DMF was added 2-pentynylmethanesulfonate (10.5 g, 65mmol) and the mixture was stirred at rt for 18 h, whereupon the mixturewas partitioned in ether:water (200 mL:200 mL). The aqueous layer wasextracted with ether (2×100 mL) and the combined organic layers werewashed sequentially with water (3×100 mL) and brine (50 mL), dried overMgSO₄, filtered and concentrated to afford 11.1 g (ca. 100%) of Compound211 as a light brown oil. ¹H NMR (400 MHz, CDCl₃) 7.80–7.90 (m, 2H),7.40–7.50 (m, 1H), 7.27–7.35 (m, 1H), 4.76 (t, J=2.1, 2H), 2.18–2.28 (m,2H), 1.13 (t, J=7.4, 3H).

1-Acetamido-3-(pent-2-ynyloxy)benzene (Compound 212, Structure 36a ofScheme VII, where R₃=ethyl, R₁=R₂=H).

A suspension of Compound 211 (15.1 g, 73.5 mmol), Zn dust (325 mesh,19.2 g, 294 mmol) and calcium chloride dihydrate (21.6 g, 147 mmol) in300 mL 95% ethanol/water was heated at reflux for 20 h, whereupon thereaction mixture was filtered while hot through Celite and rinsed with300 mL hot ethanol. The filtrate was concentrated to brown paste, whichwas partitioned between EtOAc (200 mL), water (200 mL) and 0.1 M HCl (25mL). The aqueous layer was extracted with EtOAc (2×100 mL) and thecombined organic layers were washed sequentially with water (100 mL) andbrine (100 mL), dried over MgSO₄, filtered and concentrated to 12.6 g ofa brown oil. This material was dissolved in 28 mL pyridine, cooled to 0°C., then DMAP (433 mg, 3.54 mmol) and acetic anhydride (8.68 g, 85.1mmol) was added. After 20 min, the mixture was allowed to warm to rt andthe mixture was stirred for 6 h. The reaction was quenched by theaddition of 1 mL MeOH and the reaction mixture was partitioned betweenEtOAc (200 mL) and water (200 mL). The aqueous layer was extracted withEtOAc (2×100 mL) and the combined organic layers were washedsequentially with 2N NaHSO₄ (3×100 mL), water (100 mL), NaHCO₃ (100 mL)and brine (100 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (EtOAc:hexanes 3:2) afforded 9.6 g (62%) of Compound 212.¹H NMR (400 MHz, CDCl₃) 7.42 (broad s, 1H), 7.24 (broad s, 1H), 7.20 (t,J=8.1, 1H), 7.06 (broad d, J=8.1, 1H), 6.73 (dd, J=8.1, 1.8, 1H), 4.64(t, J=2.0, 2H), 2.18–2.28 (m, 2H), 2.16 (s, 3H), 1.25 (t, J=7.4, 3H).

7-Acetamido-4-ethyl-2H-chromane (Compound 213, Structure 38a of SchemeVII, where R₃=ethyl, R₁=R₂=H).

A solution of Compound 212 (1.52 g, 7.00 mmol) in 3.5 mLN,N-diethylaniline was heated at reflux for 30 h, whereupon the brownsolution was partitioned between EtOAc (60 mL) and 1N NaHSO₄ (30 mL).The aqueous layer was extracted with EtOAc (2×30 mL) and the combinedorganic layers were washed sequentially with NaHSO₄ (2×15 mL) brine (30mL), dried over MgSO₄, filtered and concentrated. Flash chromatography(EtOAc:hexanes 1:1) afforded 0.44 g (29%) of Compound 213 as a lightamber oil. This was carried on directly by treatment with 10% Pd—C (21mg, 5 wt %) in 4.7 mL EtOAc and 4.7 mL EtOH and was stirred in 1 atm H₂for 6 h, whereupon the mixture was filtered through Celite andconcentrated to an oil. Flash chromatography (EtOAc:hexanes 1:1)afforded 0.42 g (100%, or 29% for the two-steps) of Compound 213. ¹H NMR(400 MHz, CDCl₃) δ 6.98–7.10 (m, 3H), 6.92 (s, 1H), 4.08–4.22 (m, 2H),2.60–2.70 (m, 1H), 2.14 (s, 3H), 2.00–2.10 (m, 1H), 1.75–1.90 (m, 2H),1.48–1.58 (m, 1H), 0.98 (t, J=7.4, 3H).

7-Amino-4-ethylchroman (Compound 214, Structure 38 of Scheme VII, whereR₁=R₂=H, R₃=ethyl).

A solution of Compound 213 (0.42 g, 1.9 mmol) in 3.8 mL 2N HCl washeated at reflux for 16 h, whereupon the solution was partitionedbetween EtOAc (40 mL) and saturated NaHCO₃ (20 mL). The aqueous layerwas extracted with EtOAc (2×20 mL) and the combined organic layers werewashed with brine (20 mL), dried over MgSO₄, filtered and concentrated.Flash chromatography (EtOAc:hexanes 1:1) afforded 0.30 g (90%) ofCompound 214. ¹H NMR (400 MHz, CDCl₃) 6.91 (d, J=8.0, 1H), 6.24 (dd,J=8.0, 2.4, 1H), 6.14 (d, J=2.4, 1H), 4.05–4.19 (m, 2H), 3.52 (broad s,2H), 2.55–2.65 (m, 1H), 1.95–2.05 (m, 1H), 1.70–1.85 (m, 2H), 1.42–1.52(m, 1H), 0.97 (t, J=7.4, 3H).

(±)-6,7-Dihydro-6-ethyl-4-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 210, Structure 39 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=methyl).

To a solution of Compound 214 (53 mg, 0.30 mmol) and triethylamine (60mg, 0.60 mmol) in 3 mL CH₂Cl₂ was added diketene (50 mg, 0.60 mmol) at0° C. The solution was allowed to warm to rt and after 2 h wasconcentrated to an oil. Flash chromatography (EtOAc:hexanes 3:2)afforded 46 mg (59%) of 7-acetoacetamido-4-ethylchroman, an oil. Aportion of this material was carried on directly. A solution of7-acetoacetamido-4-ethylchroman in 0.2 mL PPA (polyphosphoric acid) washeated at 100° C. for 4 h. The mixture was precipitated with water andneutralized with 6N NaOH. The mixture was extracted with EtOAc (3×20 mL)and the combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated. Flash chromatography (EtOAc:CH₂Cl₂7:3) afforded 5 mg of a solid. Final purification by HPLC (ODS semi-prepcolumn, MeOH:water 7:3, 3 mL/min) afforded 3.4 mg (36%) of Compound 210as a white solid. ¹H NMR (400 MHz, CDCl₃) 10.5 (broad s, 1H), 7.39 (s,1H), 6.68 (s, 1H), 6.35 (s, 1H), 4.17–4.30 (m, 2H), 2.72–2.82 (m, 1H),2.43 (s, 3H), 2.02–2.12 (m, 1H), 1.80–1.92 (m, 2H), 1.55–1.65 (m, 1H),1.03 (t, J=7.4, 3H).

EXAMPLE 95(±)-7,8-Dihydro-8-ethyl-4-methyl-6H-pyrano[2,3-f]quinolin-2(1H)-one(Compound 215, Structure 40 of Scheme VII, where R₂=R₅=H, R₃=ethyl,R₄=methyl)

This compound was isolated as a by-product from the preparation ofCompound 210 described in Example 94. ¹H NMR (400 MHz, CDCl₃) 10.9 (s,1H), 7.21 (d, J=8.4, 1H), 6.81 (d, J=8.4, 1H), 6.37 (s, 1H), 4.17–4.30(m, 2H), 2.67–2.77 (m, 1H), 2.65 (d, J=0.9, 3H), 2.00–2.10 (m, 1H),1.78–1.90 (m, 2H), 1.50–1.60 (m, 1H), 1.00 (t, J=7.3, 3H).

EXAMPLE 96(±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 216, Structure 39 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=trifluoromethyl)

A solution of Compound 214 (Structure 38 of Scheme VII, where R₁=R₂=H,R₃=ethyl) (14 mg, 0.079 mmol) and ethyl 4,4,4-trifluoroacetoacetate (17mg, 0.095 mmol) in 0.8 mL benzene was heated at reflux for 14 h. Thesolution was concentrated and purified by flash chromatography(hexanes:EtOAc 3:2) to afford 21 mg of an oil. This was treated with PPAand heated at 100° C. for 6 h. The dark brown sludge was partitionedbetween water (20 mL) and ethyl acetate (20 mL). The aqueous layer wasextracted with EtOAc (2×20 mL) and the combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc 4:1) afforded 5.7 mg (29%) of a whitesolid. Final purification by HPLC (ODS semi-prep column, MeOH:water 7:3,3 mL/min) afforded 3.4 mg (17%) of Compound 216 as a white solid. ¹H NMR(400 MHz, CDCl₃) 11.2 (broad s 1H), 7.54 (s, 1H), 6.86 (s, 1H), 6.77 (s,1H), 4.22–4.32 (m, 2H), 2.75–2.85 (m, 1H), 2.05–2.15 (m, 1H), 1.80–1.90(m, 2H), 1.55–1.65 (m, 2H), 1.03 (t, J=7.3, 3H).

EXAMPLE 97(−)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 217, Structure 39 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=trifluoromethyl) and(+)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 218, Structure 39 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=trifluoromethyl)

Compound 216 was separated into its constitutive enantiomers via chiralHPLC on a semi-prep Chiralcel AD column (hexanes:isopropanol 97:3, 5.0mL/min) to afford Compound 217 and Compound 218. Data for Compound 217:t_(R) 46.5 min (hexanes:isopropanol 97:3). Data for Compound 218: t_(R)58.3 min (hexanes:isopropanol 97:3).

EXAMPLE 98(±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 219, Structure 39 of Scheme VII, where R₁=R₂=H, R₃=ethyl,R₄=trifluoromethyl, R₅=F)

A solution of Compound 214 (Structure 38 of Scheme VII, where R₁=R₂=H,R₃=ethyl) (100 mg, 0.56 mmol) and ethyl2,4,4,4-tetrafluoro-3,3-dihydroxybutanoate (185 mg, 0.84 mmol) washeated at 130° C. for 20 h. The mixture was passed through a plug ofsilica gel (EtOAc) and concentrated to a brown oil. This oil was treatedwith 1.5 mL PPA and heated at 1 00° C. for 6 h, then precipitated withcold water and neutralized with 6N NaOH. The mixture was extracted withEtOAc (3×25 mL) and the combined organic layers were washed with brine(25 mL), dried over MgSO₄, filtered and concentrated. Flashchromatography (CH₂Cl₂:EtOAc 4:1) afforded 70 mg (48%) of Compound 219as a white solid. ¹HNMR (400 MHz, CDCl₃) 11.8 (broad s, 1H), 7.58 (s,1H), 6.84 (s, 1H), 4.22–4.32 (m, 2H), 2.78–2.88 (m, 1H), 2.05–2.15 (m,1H), 1.80–1.95 (m, 2H), 1.55–1.68 (m, 1H), 1.03 (t, J=7.4, 3H).

EXAMPLE 99(±)-6,7-Dihydro-6-ethyl-4-trifluoromethyl-1-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 220, Structure 41 of Scheme VII, where R₁=R₂=R₅=H, R₃=ethyl,R₄=trifluoromethyl)

General Method: N-Methylation of a pyridone with sodium hydride and MeI.To a suspension of the pyridone (1 equiv) and NaH (60% mineral oildispersion, 1.2–2.5 equiv) in THF (0.05 M) was added MeI (1.2–2.5equiv). The mixture was stirred for 24 h and partitioned between CH₂Cl₂and pH 7 phosphate buffer. The aqueous layer was extracted with CH₂Cl₂and the combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated and purified as indicated.

This compound was prepared according to the General Method describedabove from Compound 216 (Structure 39 of Scheme VII, where R₁=R₂=R₅=H,R₃=ethyl, R₄=trifluoromethyl) (7.2 mg, 0.024 mmol), NaH (1.0 mg, 0.029)and MeI (2 μL, 0.029 mmol) in 51% yield (3.8 mg) after flashchromatography (CH₂Cl₂:MeOH 24:1). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (broads, 1H), 6.90 (s, 1H), 6.81 (s, 1H), 4.24–4.36 (m, 2H), 3.65 (s, 3H),2.75–2.85 (m, 1H), 2.07–2.17 (m, 1H), 1.80–1.95 (m, 2H), 1.58–1.68 (m,1H), 1.04 (t, J=7.4, 3H).

EXAMPLE 100(±)-6,7-Dihydro-6-ethyl-3-fluoro-4-trifluoromethyl-1-methyl-8H-pyrano[3,2-g]quinolin-2(1H)-one(Compound 221, Structure 41 of Scheme VII, where R₁=R₂=H, R₃=ethyl,R₄=trifluoromethyl, R₅=F)

This compound was prepared according to General Method in Example 99from Compound 219 (Structure 39 of Scheme VII, where R₁=R₂=H, R₃=ethyl,R₄=trifluoromethyl, R₅=F) (11 mg, 0.034 mmol), NaH (3.0 mg, 0.085 mmol)and MeI (5.2 μL, 0.085 mmol) in 30% yield (3.4 mg) after purification byflash chromatography (CH₂Cl₂:MeOH 24:1). ¹H NMR (400 MHz, CDCl₃) 7.61(s, 1H), 6.80 (s, 1H), 4.22–4.36 (m, 2H), 3.70 (s, 3H), 2.77–2.87 (m,1H), 2.05–2.15 (m, 1H), 1.80–1.95 (m, 2H), 1.55–1.65 (m, 1H), 1.03 (t,J=7.4, 3H).

EXAMPLE 101(±)-6,7-Dihydro-6-ethyl-2,4-bis(trifluoromethyl)-8H-pyrano[3,2-g]quinoline(Compound 222, Structure 42 of Scheme VII, where R₁=R₂=H, R₃=ethyl)

To a solution of Compound 214 (Structure 38 of Scheme VII, whereR₁=R₂=H, R₃=ethyl) (30 mg, 0.17 mmol) and1,1,1,5,5,5-hexafluoropentan-2,4-dione in 0.8 mL toluene was heated at60° C. for 18 h, whereupon p-toluensulfonic acid monohydrate (6.4 mg,0.034 mmol) was added and the solution heated at 60° C. for 6 h. Themixture was concentrated to an oil and purified by flash chromatography(CH₂Cl₂:hexanes 1:1) to afford 29 mg (49%) of Compound 222 as a yellowoil. ¹H NMR (400 MHz, CDCl₃) 7.94 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H),4.32–4.44 (m, 2H), 2.98–3.08 (m, 1H), 2.14–2.24 (m, 1H), 1.88–2.04 (m,2H), 1.68–1.86 (m, 1H), 1.08 (t, J=7.4, 3H).

EXAMPLE 102 6,8,8-Trimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin(Compound 223, Structure 47 of Scheme VIII, where R=methyl)

2,2-Dimethyl-7-hydroxy-4-chromanone (Compound 224, Structure 44 ofScheme VIII).

1,3-Resorcinol (Structure 43 of Scheme VIII) (1 g, 9.1 mmol) and3,3-dimethylacrylic acid (909 mg, 9.1 mmol) were dissolved intrifluoroacetic acid (10 mL) and stirred at 80° C. for 2 h. The reactionwas made basic with 20% KOH to pH 7. The mixture was partitioned betweenEtOAc (50 mL) and water (50 mL). The aqueous was extracted with EtOAc(2×50 mL). The combined organic layers were washed sequentially withwater (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (25% EtOAc/hexanes) afforded 1.5 g(87%) of Compound 224. ¹H NMR (400 MHz, acetone-d₆) 9.26 (bs, 1H), 7.66(d, J=8.7, 1H), 6.51 (dd, J=8.7, 2.1, 1H), 6.33 (d, J=2.1, 1H), 2.64 (s,2H), 1.42 (s, 6H).

2,2,4-Trimethyl-4,7-dihydroxychroman (Compound 225, Structure 45 ofScheme VIII, where R=methyl).

Compound 224 (250 mg, 1.3 mmol) was dissolved in diethyl ether andcooled to 0° C. Methyl magnesium bromide (3.0M, 2.6 mL, 7.8 mmol) wasadded slowly via syringe. The reaction was allowed to warm to roomtemperature. After 2 h the reaction was quenched with water andpartitioned between EtOAc (25 mL) and water (25 mL). The aqueous wasextracted with EtOAc (2×25 mL). The combined organic layers were washedsequentially with water (25 mL) and brine (25 mL), dried over Na₂SO₄,filtered and concentrated. Flash chromatography (30% EtOAc/hexanes)afforded 220 mg (81%) of Compound 225. ¹H NMR (400 MHz, acetone-d₆) 8.16(s, 1H), 7.32 (d, J=8.5, 1H), 6.4 (dd, J=8.5, 2.5, 1H), 6.2 (d, J=2.5,1H), 3.7 (s, 1H), 2.03(s, 2H), 1.5 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H).

2,2,4-Trimethyl-7-hydroxy-2H-chromene (Compound 226, Structure 46 ofScheme VIII, where R=methyl).

2,2,4-trimethyl-4,7-dihydroxychroman (225) (220 mg, 1.06 mmol), wasdissolved in CH₂Cl₂ (5 mL) and treated with p-toluene sulfonic acidmonohydrate (25 mg, 0.13 mmol). The resulting solution was stirred at rtfor 2 h. The reaction was quenched with NaHCO₃ (sat.) to pH 7 and themixture was partitioned between EtOAc (25 mL) and water (25 mL). Theaqueous was extracted with EtOAc (2×25 mL). The combined organic layerswere washed sequentially with water (25 mL) and brine (25 mL), driedover Na₂SO₄, filtered and concentrated. Flash chromatography (15%EtOAc/hexanes) afforded 135 mg (67%) of Compound 226. ¹H NMR (400 MHz,acetone-d₆) 8.37 (s, 1H), 7.0 (dd, J=8.4, 2.4, 1H), 6.26 (d, J=2.4, 1H),5.32 (s, 1H), 1.94 (s, 3H), 1.33 (s, 6H).

6,8,8-Trimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin (Compound223, Structure 47 of Scheme VIII, where R=methyl).

Compound 226 (60 mg, 0.31 mmol) and ethyl-4,4,4-trifluoroacetoacetate(116 mg, 0.63 mmol) were dissolved in toluene and treated with POCl₃ (97mg, 0.63 mmol) and stirred at 100° C. for 8 h. The reaction was allowedto cool down to rt. The reaction was quenched slowly with dropwiseaddition of water and partitioned between EtOAc (25 mL) and water (25mL). The aqueous was extracted with EtOAc (3×25 mL). The combinedorganic layers were washed sequentially with water (25 mL) and brine (25mL), dried over Na₂SO₄, filtered and concentrated. Flash chromatography(5% EtOAc/hexanes) afforded 40 mg (41%) of Compound 223. ¹H NMR (400MHz, acetone-d₆) 7.43 (s, 1H), 6.8 (s, 1H), 6.7 (s, 1H), 5.75 (s, 1H),2.08 (s, 3H), 1.46 (s, 6H).

EXAMPLE 1036-Ethyl-8,8-dimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin(Compound 227, Structure 47 of Scheme VIII, where R=ethyl)

4-Ethyl-2,2-dimethyl-7-hydroxy-2H-chromene (Compound 228, Structure 46of Scheme VIII, where R=ethyl).

Compound 224 (200 mg, 1.04 mmol) was dissolved in diethyl ether andcooled to 0° C. Ethyl magnesium bromide (3.0M, 1.7 mL, 5.2 mmol) wasadded slowly via syringe. The reaction was allowed to warm to roomtemperature. After 2 h the reaction was quenched with water andpartitioned between EtOAc (25 mL) and water (25 mL). The aqueous wasextracted with EtOAc (2×25 mL). The combined organic layers were washedsequentially with water (25 mL) and brine (25 mL), dried over Na₂SO₄,filtered and concentrated. The crude material was dissolved in CH₂Cl₂ (5mL) and treated with p-toluene sulfonic acid monohydrate (25 mg, 0.13mmol). The resulting solution was stirred at rt for 2 h. The reactionwas quenched with NaHCO₃ (sat) to pH 7 and the mixture was partitionedbetween EtOAc (25 mL) and water (25 mL). The aqueous was extracted withEtOAc (2×25 mL). The combined organic layers were washed sequentiallywith water (25 mL) and brine (25 mL), dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (15% EtOAc/hexanes) afforded 220 mg(81%) of Compound 228. ¹H NMR (400 MHz, acetone-d₆) 8.4 (bs, 1H), 7.15(d, J=8.5, 1H), 6.38 (dd, J=8.5, 2.5, 1H), 6.28 (d, J=2.5, 1H), 5.3 (s,1H), 2.34 (q, J=7.4, 2H), 1.11 (t, J=7.4, 3H).

6-Ethyl-8,8-dimethyl-4-trifluoromethyl-8H-pyrano[3,2-g]coumarin(Compound 227, Structure 47 of Scheme VIII, where R=ethyl).

Compound 228 (60 mg, 0.29 mmol) and ethyl-4,4,4-trifluoroacetoacetate(107 mg, 0.58 mmol) were dissolved in toluene and treated with POCl₃ (90mg, 0.58 mmol) and stirred at 100° C. for 8 h. The reaction was allowedto cool down to rt. The reaction was quenched slowly with dropwiseaddition of water and partitioned between EtOAc (25 mL) and water (25mL). The aqueous was extracted with EtOAc (3×25 mL). The combinedorganic layers were washed sequentially with water (25 mL) and brine (25mL), dried over Na₂SO₄, filtered and concentrated. Flash chromatography(5% EtOAc/hexanes) afforded 29 mg (31%) of Compound 227. ¹H NMR (400MHz, acetone-d₆) 7.48 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 5.74 (s, 1H),2.48 (q, J=7.4, 2H), 1.47 (s, 6H), 1.18 (t, J=7.5, 3H).

EXAMPLE 104(±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one(Compound 228, Structure 33a of Scheme VI, where R₁=hydroxymethyl, n=0)

Compound 228 was prepared according to a similar procedure described inExample 81: ¹H NMR (500 MHz, acetone-d₆) 11.02 (bs, 1H), 7.39 (d, J=8.8,1H), 7.10 (d, J=8.8, 1H), 7.01 (s, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 3.55(m, 1H), 1.42 (d, J=6.1, 2H).

EXAMPLE 105(±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one(Compound 229, Structure 34a of Scheme VI, where R₁=hydroxymethyl,R₂=ethyl, n=0)

Compound 229 was prepared by ethylation of Compound 228: ¹H NMR (500MHz, CDCl₃) 11.71 (bs, 1H), 7.21 (d, J=8.5, 1H), 7.15 (s, 1H), 6.80 (d,J=8.5, 1H), 3.74 (m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.78(m, 1H), 1.34 (d, J=5.9, 2H), 1.11 (t, J=6.5, 3H).

EXAMPLE 1067,8-Dihydro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one(Compound 230, Structure 34 of Scheme VI, where R₁=H,R₂=2,2,2-trifluoroethyl, n=0)

Compound 230 was prepared according to a similar procedure described inExample 81: ¹H NMR (500 MHz, acetone-d₆) 11.10 (bs, 1H), 7.32 (s, 1H),6.82 (s, 1H), 6.80 (s, 1H), 4.13 (q, J=10.0, 2H), 3.73 (t, J=8.5, 1H),3.22 (t, J=8.5, 1H).

EXAMPLE 1076-(2,2,2-Trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one(Compound 231, Structure 34b of Scheme VI, where R₁=R₃=H,R₂=2,2,2-trifluoroethyl)

Compound 231 was prepared by oxidation of Compound 230: ¹H NMR (500 MHz,acetone-d₆) 10.93 (bs, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=3.5,1H), 6.87 (s, 1H), 6.71 (dd, J=3.5 and 1.0, 1H), 5.31 (q, J=9.0, 2H).

EXAMPLE 1088-Chloro-6-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[2,3-g]quinolin-2(1H)-one(Compound 232, Structure 34b of Scheme VI, where R₁=H, R₃=Cl,R₂=2,2,2-trifluoroethyl)

Compound 232 was prepared by chloronation of Compound 232: ¹H NMR (500MHz, acetone-d₆) 11.04 (bs, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.70 (s,1H), 6.95 (s, 1H), 5.36 (q, J=9.0, 2H).

EXAMPLE 1095-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one(Compound 233, Structure 19 of Scheme III, where R₄=H, R₃=methyl,R₅=2,2,2-trifluoroethyl)

This compound was isolated as an over oxidation product of Compound 150(Structure 18 of Scheme III, where R₁=R₂=methyl) by the generaloxidation procedure described in Example 49: ¹H NMR (500 MHz, DMSO-d₆)12.2 (bs, 1H), 7.95 (d, J=8.8, 1H), 7.27 (d, J=8.8, 1H), 6.99 (s, 1H),6.66 (s, 1H), 5.27 (q, J_(H-F)=8.8, 2H), 2.53 (s, 3H).

EXAMPLE 1106-Formyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 234, Structure 19 of Scheme III, where R₄=formyl, R₃=methyl,R₅=2,2,2-trifluoroethyl)

This compound was prepared by the general oxidation procedure describedin Example 49 from Compound 150 (Structure 18 of Scheme III, whereR₁=R₂=methyl). ¹H NMR (500 MHz, DMSO-d₆) 11.9 (bs, 1H), 10.18 (s, 1H),8.06 (d, J=8.8, 1H), 7.52 (d, J=8.8, 1H), 7.07 (s, 1H), 5.65 (q,J_(H-F)=8.8, 2H), 2.62 (s, 3H).

EXAMPLE 1115,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one(Compound 235, Structure 19 of Scheme III, where R₄=R₃=methyl,R₅=2,2-difluorovinyl)

This compound was isolated as an over oxidation product of Compound 150(Structure 18 of Scheme III, where R₁=R₂=methyl) by the generaloxidation procedure described in Example 49: ¹H NMR (500 MHz, DMSO-d₆)12.4 (bs, 1H), 7.76 (d, J=8.8, 1H), 7.65 (d, J=8.8, 1H), 7.16 (s, 1H),5.05–5.00 (m, 1H), 2.45 (d, J=0.9, 3H), 1.96 (s, 3H).

EXAMPLE 112

Steroid Receptor Activity

Utilizing the “cis-trans” or “co-transfection” assay described by Evanset al., Science, 240:889–95 (May 13, 1988), the disclosure of which isincorporated by reference herein, the compounds of the present inventionwere tested and found to have strong, specific activity as agonists,partial agonists and antagonists of AR. This assay is described infurther detail in U.S. Pat. Nos. 4,981,784 and 5,071,773, thedisclosures of which are incorporated herein by reference.

The co-transfection assay provides a method for identifying functionalagonists and partial agonists which mimic, or antagonists which inhibit,the effect of native hormones and quantifying their activity forresponsive IR proteins. In this regard, the co-transfection assay mimicsan in vivo system in the laboratory. Importantly, activity in theco-transfection assay correlates very well with known in vivo activity,such that the co-transfection assay functions as a qualitative andquantitative predictor of a tested compounds in vivo pharmacology. See,e.g., T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 773 (1992),the disclosure of which is herein incorporated by reference.

In the co-transfection assay, a cloned cDNA for an IR (e.g., human PR,AR or GR) under the control of a constitutive promoter (e.g., the SV 40promoter) is introduced by transfection (a procedure to induce cells totake up foreign genes) into a background cell substantially devoid ofendogenous IRs. This introduced gene directs the recipient cells to makethe IR protein of interest. A second gene is also introduced(co-transfected) into the same cells in conjunction with the IR gene.This second gene, comprising the cDNA for a reporter protein, such asfirefly luciferase (LUC), controlled by an appropriate hormoneresponsive promoter containing a hormone response element (HRE). Thisreporter plasmid functions as a reporter for thetranscription-modulating activity of the target IR. Thus, the reporteracts as a surrogate for the products (mRNA then protein) normallyexpressed by a gene under control of the target receptor and its nativehormone.

The co-transfection assay can detect small molecule agonists orantagonists of target IRs. Exposing the transfected cells to an agonistligand compound increases reporter activity in the transfected cells.This activity can be conveniently measured, e.g., by increasingluciferase production, which reflects compound-dependent, IR-mediatedincreases in reporter transcription. A partial agonist's activity can bedetected in a manner similar to that of the full agonist, except thatthe maximum measured activity, e.g., luciferase production, is less thanthat of an agonist standard. For example, for AR, a partial agonist canbe detected by measuring increased luciferase production, but themaximum effect at high concentration is less than the maximum effect fordihydrotestosterone. To detect antagonists, the co-transfection assay iscarried out in the presence of a constant concentration of an agonist tothe target IR (e.g., progesterone for PR) known to induce a definedreporter signal. Increasing concentrations of a suspected antagonistwill decrease the reporter signal (e.g., luciferase production). Theco-transfection assay is therefore useful to detect both agonists andantagonists of specific IRs. Furthermore, it determines not only whethera compound interacts with a particular IR, but whether this interactionmimics (agonizes) or blocks (antagonizes) the effects of the nativeregulatory molecules on target gene expression, as well as thespecificity and strength of this interaction.

The activity of selected steroid receptor modulator compounds of thepresent invention were evaluated utilizing the co-transfection assay andin standard IR binding assays, according to the following illustrativeExamples.

Co-Transfection Assay

CV-1 cells (African green monkey kidney fibroblasts) were cultured inthe presence of Dulbecco's Modified Eagle Medium (DMEM) supplementedwith 10% charcoal resin-stripped fetal bovine serum then transferred to96-well microtiter plates one day prior to transfection.

To determine AR agonist and antagonist activity of the compounds of thepresent invention, the CV-1 cells were transiently transfected bycalcium phosphate coprecipitation according to the procedure of Bergeret al., 41 J. Steroid Biochem. Mol. Biol., 733 (1992) with the followingplasmids: pShAR (5 ng/well), MTV-LUC reporter (100 ng/well), pRS-β-Gal(50 ng/well) and filler DNA (PGEM; 45 ng/well). The receptor plasmid,pRShAR, contains the human AR under constitutive control of the SV-40promoter, as more fully described in J. A. Simental et al.,“Transcriptional activation and nuclear targeting signals of the humanandrogen receptor”, 266 J. Biol. Chem., 510 (1991).

The reporter plasmid, MTV-LUC, contains the cDNA for firefly luciferase(LUC) under control of the mouse mammary tumor virus (MTV) long terminalrepeat, a conditional promoter containing an androgen response element.See e.g., Berger et al. supra. In addition, pRS-β-Gal, coding forconstitutive expression of E. coli β-galactosidase (β-Gal), was includedas an internal control for evaluation of transfection efficiency andcompound toxicity.

Six hours after transfection, media was removed and the cells werewashed with phosphate-buffered saline (PBS). Media containing referencecompounds (i.e. progesterone as a PR agonist, mifepristone ((11β,17β)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one:RU486; Roussel Uclaf) as a PR antagonist; dihydrotestosterone (DHT;Sigma Chemical) as an AR agonist and 2-OH-flutamide (the activemetabolite of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide;Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER agonistand ICI 164,384(N-butyl-3,17-dihydroxy-N-methyl-(7-α,17-β)-estra-1,3,5(10)-triene-7-undecanamide;ICI Americas) as an ER antagonist; dexamethasone (Sigma) as a GR agonistand RU486 as a GR antagonist; and aldosterone (Sigma) as a MR agonistand spironolactone((7-α-[acetylthio]-17-α-hydroxy-3-oxopregn-4-ene-21-carboxylic acidδ-lactone; Sigma) as an MR antagonist) and/or the modulator compounds ofthe present invention in concentrations ranging from 10⁻¹² to 10⁻⁵ Mwere added to the cells. Three to four replicates were used for eachsample. Transfections and subsequent procedures were performed on aBiomek 1000 automated laboratory work station.

After 40 hours, the cells were washed with PBS, lysed with a TritonX-100-based buffer and assayed for LUC and β-Gal activities using aluminometer or spectrophotometer, respectively. For each replicate, thenormalized response (NR) was calculated as:LUC response/β-Gal rate

-   -   where β-Gal rate=β-Gal·1×10⁻⁵/β-Gal incubation time.

The mean and standard error of the mean (SEM) of the NR were calculated.Data was plotted as the response of the compound compared to thereference compounds over the range of the dose-response curve. Foragonist experiments, the effective concentration that produced 50% ofthe maximum response (EC₅₀) was quantified. Agonist efficacy was afunction (%) of LUC expression relative to the maximum LUC production bythe reference agonist for PR, AR, ER, GR or MR. Antagonist activity wasdetermined by testing the amount of LUC expression in the presence of afixed amount of DHT as an AR agonist and progesterone as a PR agonist atthe EC₅₀ concentration. The concentration of test compound thatinhibited 50% of LUC expression induced by the reference agonist wasquantified (IC₅₀). In addition, the efficacy of antagonists wasdetermined as a function (%) of maximal inhibition.

IR Binding Assay

AR Binding: For the whole cell binding assay, COS-1 cells in 96-wellmicrotiter plates containing DMEM-10% FBS were transfected as describedabove with the following plasmid DNA: pRShAR (2 ng/well), pRS-β-Gal (50ng/well) and pGEM (48 ng/well). Six hours after transfection, media wasremoved, the cells were washed with PBS and fresh media was added. Thenext day, the media was changed to DMEM-serum free to remove anyendogenous ligand that might be complexed with the receptor in thecells.

After 24 hours in serum-free media, either a saturation analysis todetermine the K_(d) for tritiated dihydrotestosterone (³H-DHT) on humanAR or a competitive binding assay to evaluate the ability of testcompounds to compete with ³H-DHT for AR was performed. For thesaturation analysis, media (DMEM-0.2% CA-FBS) containing ³H-DHT (inconcentrations ranging from 12 nM to 0.24 nM) in the absence (totalbinding) or presence (non-specific binding) of a 100-fold molar excessof unlabeled DHT were added to the cells. For the competitive bindingassay, media containing 1 nM ³H-DHT and test compounds in concentrationsranging from 10⁻¹⁰ to 10⁻⁶ M were added to the cells. Three replicateswere used for each sample. After three hours at 37° C., an aliquot ofthe total binding media at each concentration of ³H-DHT was removed toestimate the amount of free ³H-DHT. The remaining media was removed, thecells were washed three times with PBS to remove unbound ligand andcells were lysed with a Triton X-100-based buffer. The lysates wereassayed for amount of bound ³H-DHT and β-Gal activity using ascintillation counter or spectrophotometer, respectively.

For the saturation analyses, the difference between the total bindingand the nonspecific binding, normalized by the β-Gal rate, was definedas specific binding. The specific binding was evaluated by Scatchardanalysis to determine the K_(d) for ³H-DHT. See e.g., D. Rodbard,“Mathematics and statistics of ligand assays: an illustrated guide” In:J. Langon and J. J. Clapp, eds., Ligand Assay, Masson Publishing U.S.A.,Inc., New York, pp. 45–99, (1981), the disclosure of which is hereinincorporated by reference. For the competition studies, the data wasplotted as the amount of ³H-DHT (% of control in the absence of testcompound) remaining over the range of the dose-response curve for agiven compound. The concentration of test compound that inhibited 50% ofthe amount of ³H-DHT bound in the absence of competing ligand wasquantified (IC₅₀) after log-logit transformation. The K_(i) values weredetermined by application of the Cheng-Prusoff equation to the IC₅₀values, where:

$K_{i} = \frac{{IC}_{50}}{{\left( {1 + \left\lbrack {}^{3}{H\text{-}{DHT}} \right\rbrack} \right)/K_{d}}\mspace{14mu}{{for}\mspace{14mu}}^{3}H\text{-}{DHT}}$

After correcting for non-specific binding, IC₅₀ values were determined.The IC₅₀ value is defined as the concentration of competing ligandneeded to reduce specific binding by 50%. The IC₅₀ value was determinedgraphically from a log-logit plot of the data. The K_(i) values weredetermined by application of the Cheng-Prusoff equation to the IC₅₀values, the labeled ligand concentration and the K_(d) of the labeledligand.

The antagonist and binding activity assay results of selected androgenreceptor modulator compounds of present invention and the standardreference compounds on AR, as well as the cross-reactivity of selectedcompounds on the PR, ER, MR and GR receptors shown in Tables 1–2 below.Efficacy is reported as the percent maximal response observed for eachcompound relative to the reference agonist and antagonist compoundsindicated above. Also reported in Tables 1–2 for each compound is itsantagonist potency or IC₅₀ (which is the concentration (nM), required toreduce the maximal response by 50%), its agonist potency or EC₅₀ (nM).

TABLE 1 Cotransfection and competitive binding data of selected androgenreceptor modulator compounds of present invention and the referenceagonist compound, dihydrotestosterone (DHT) and reference antagonistscompound, 2-hydroxyflutamide (Flut) and Casodex (Cas), on AR. AR AgonistAR Antagonist AR CV-1 Cells CV-1 Cells Binding Cmpd Efficacy PotencyEfficacy Potency K_(i) No. (%) (nM) (%) (nM) (nM) 104 78 183 50 1.8 15105 57 32 na na 45 106 108 12 na na 45 108 66 24 na na 6.7 109 97 13 nana 1.2 110 106 21 na na 21 112 na na 75 10 119 113 na na 65 316 529 114na na 81 6.6 81 119 94 2.5 na na 2.6 120 117 4.5 na na 12 121 97 43 nana 7.6 122 59 34 na na 21 123 104 1.4 na na 14 125 121 38 na na 1.3 12653 11 na na 2.3 127 66 25 na na 6.3 129 79 1.6 na na 3.2 132 70 4.8 nana 21 134 70 4.2 na na 6.8 137 77 145 na na 107 141 46 86 44 34 97 144na na 53 23 1000 146 38 49 66 1 75 149 na na 81 25 127 150 95 2.1 na na4.0 151 36 120 57 5.9 48 152 74 4.9 na na 67 153 76 7.6 na na 1.7 155 599.4 na na 7.4 158 59 7.9 na na 7.1 159 na na 66 15 989 161 27 238 66 1030 162 71 20 na na 113 163 na na 37 8.2 1000 166 96 24 na na 17 172 8919 na na 12 173 41 138 56 1 80 175 na na 78 11 239 177 na na 98 790 31178 24 21 48 50 900 179 91 1.3 na na 4.1 182 na an 81 13 1000 195 78 11na na 20 197 66 12 na na 79 198 47 1.7 na na 58 199 70 42 na na 236 20176 11 na na 10 202 na na 92 146 1000 206 na na 90 175 1000 215 28 207077 17 47 216 55 11 28 4300 8.1 217 na na 85 64 1000 218 82 10 na na 4.1220 na na 67 23 1000 221 na na 78 311 29 223 na na 66 41 37 227 na na 7525 33 HO-Flut na na 83 25 34 Casodex na na 81 201 117 DHT 100 4.3 na na1.7 na = not active (i.e. efficacy of <20 and potency of >10,000); nd =not determined.Pharmacological and other Applications

As will be discernible to those skilled in the art, the androgen orprogesterone receptor modulator compounds of the present invention canbe readily utilized in pharmacological applications where AR or PRantagonist or agonist activity is desired and where it is desired tominimize reactivities with other steroid receptor related IRs. In vivoapplications of the invention include administration of the disclosedcompounds to mammalian subjects and in particular to humans.

The following Example provides illustrative pharmaceutical compositionformulations:

EXAMPLE 113

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) COMPOUND 153 140 Starch, dried 100 Magnesiumstearate 10 Total 250 mgThe above ingredients are mixed and filled into hard gelatin capsules in250 mg quantities.

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) COMPOUND 153 140 Cellulose, microcrystalline 200Silicon dioxide, fumed 10 Stearic acid 10 Total 360 mgThe components are blended and compressed to form tablets each weighing360 mg.

Tablets, each containing 60 mg of active ingredient, are made asfollows:

Quantity (mg/tablet) COMPOUND 153 60 Starch 45 Cellulose,microcrystalline 35 Polyvinylpyrrolidone (PVP) 4 (as 10% solution inwater) Sodium carboxymethyl starch (SCMS) 4.5 Magnesium stearate 0.5Talc 1.0 Total 150 mgThe active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed withthe resultant powders, which are then passed through a No. 14 mesh U.S.sieve. The granules so produced are dried at 50° C. and passed through aNo. 18 mesh U.S. sieve. The SCMS, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve and then added to thegranules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Suppositories, each containing 225 mg of active ingredient, may be madeas follows:

Quantity (mg/suppository) COMPOUND 153 225 Saturated fatty acidglycerides 2,000 Total 2,225 mgThe active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of normal 2 g capacity and allowed to cool.

An intravenous formulation may be prepared as follows:

Quantity COMPOUND 153 100 mg isotonic saline 1000 mL glycerol 100 mLThe compound is dissolved in the glycerol and then the solution isslowly diluted with isotonic saline. The solution of the aboveingredients is then administered intravenously at a rate of 1 mL perminute to a patient.

The present invention includes any combination of the various speciesand subgeneric groupings falling within the generic disclosure. Thisinvention therefore includes the generic description of the inventionwith a proviso or negative limitation removing any subject matter fromthe genus, regardless of whether or not the excised material isspecifically recited herein.

While in accordance with the patent statutes, description of the variousembodiments and processing conditions have been provided, the scope ofthe invention is not to be limited thereto or thereby. Modifications andalterations of the present invention will be apparent to those skilledin the art without departing from the scope and spirit of the presentinvention.

Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims, rather than by the specific exampleswhich have been presented by way of example.

1. A compound of the formula:

wherein: R¹ is selected from among hydrogen, F, Cl, Br, I, NO₂, OR¹²,SR¹², SOR¹², SO₂R¹², NR¹²R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl and C₁–C₈heteroalkyl, wherein the haloalkyl and heteroalkyl groups are optionallysubstituted; R² is selected from among hydrogen, F, Cl, Br, I, CF₃,CHF₂, CH₂F, CF₂Cl, CN, CF₂OR¹², CH₂OR, OR¹², SR¹², SOR¹², SO₂R¹²,NR¹²R¹³, substituted C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl,C₂–C₈ alkenyl and C₂–C₈ alkynyl, wherein the alkyl, haloalkyl,heteroalkyl, alkenyl and alkynyl groups are optionally substituted; R³is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁴ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; R⁵ isselected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁶ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; R⁷ isselected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁸ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; or R³and R⁵ taken together form a bond; or R⁵ and R⁷ taken together form abond; or R⁴ and R⁶ taken together form a three- to eight-memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringis optionally substituted; or R⁶ and R⁸ taken together form a three- toeight-membered saturated or unsaturated carbocyclic ring, wherein thecarbocyclic ring is optionally substituted; R⁹ and R¹⁰ eachindependently is selected from among hydrogen, F, Cl, Br, I, CN, OR¹²,NR¹²R¹³, C_(m)(R¹²)_(2m)OR¹³, SR¹², SOR¹², SO₂R¹², NR¹²C(O)R¹³, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl and arylalkyl, wherein thealkyl, haloalkyl, heteroalkyl and arylalkyl groups are optionallysubstituted; R¹¹ is selected from among hydrogen, F, Br, Cl, I, CN,OR¹⁴, NR¹⁴R¹³, and SR¹⁴; R¹² and R¹³ each independently is selected fromthe group of hydrogen, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl,C₂–C₈ alkenyl, C₂–C₈ alkynyl, heteroaryl and aryl, wherein the alkyl,haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups areoptionally substituted; R¹⁴ is selected from among hydrogen, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, aryl, heteroaryl, C(O)R¹⁵,CO₂R¹⁵ and C(O)NR¹⁵R¹⁶, wherein the alkyl, haloalkyl, heteroalkyl, aryland heteroaryl groups are optionally substituted; R¹⁵ and R¹⁶ eachindependently is selected from among hydrogen, C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; W is O or S; X is N{R¹⁴};Y is selected from among O, S, N{R¹²} and NO{R¹²}; Z is N{R¹²}; n is 0;and m is 0 or 1; or a pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1, wherein R² is selected from among F, Cl,Br, CF₃, CF₂Cl, CF₂H, CFH₂, substituted C₁–C₆ alkyl, C₁–C₆ haloalkyl andC₁–C₆ heteroalkyl, wherein the haloalkyl and heteroalkyl groups areoptionally substituted.
 3. A compound according to claim 1, wherein R²is selected from among CF₂OR¹², CH₂OR¹², OR¹², SR¹², SOR¹², SO₂R¹² andNR¹²R¹³.
 4. A compound according to claim 1, wherein R² is selected fromamong hydrogen, F, Cl, Br, CF₃, CF₂Cl, CF₂H, CFH₂, substituted C₁–C₄alkyl, C₁–C₄ haloalkyl, C₁–C₄ heteroalkyl, C₂–C₄ alkenyl and C₂–C₄alkynyl, wherein the haloalkyl, heteroalkyl, alkenyl and alkynyl groupsare optionally substituted.
 5. A compound according to claim 4, whereinR² is selected from among F, Cl, CF₃, CF₂Cl, CF₂H, CFH₂ and substitutedC₁–C₄ alkyl.
 6. A compound according to claim 1, wherein R⁹ and R¹⁰ eachindependently is selected from among hydrogen, F, Cl, Br, C₁–C₆ alkyl,C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 7. A compound accordingto claim 6, wherein R⁹ and R¹⁰ each independently is selected from amonghydrogen, F, Cl, C₁–C₄ alkyl, C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted.
 8. A compound according to claim 7, wherein R⁹ and R¹⁰ eachindependently is selected from among hydrogen, F and CH₃.
 9. A compoundaccording to claim 1, wherein R¹ is selected from among hydrogen, F, Cl,Br, I, substituted C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl,wherein the haloalkyl and heteroalkyl groups are optionally substituted.10. A compound according to claim 9, wherein R¹¹ is selected from amonghydrogen, F, Cl, C₁–C₄ alkyl, C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted.
 11. A compound according to claim 9, wherein R¹ is hydrogenor F.
 12. A compound according to claim 1, wherein Y is O or S.
 13. Acompound according to claim 12, wherein Y is O.
 14. A compound accordingto claim 1, wherein R¹¹ is selected from among F, Cl, CN, OR¹⁴, NR¹⁴R¹³and SR¹⁴.
 15. A compound according to claim 14, wherein R¹¹ is selectedfrom among F, Cl, OR¹⁴, SR¹⁴ and NR¹⁴R¹³.
 16. A compound according toclaim 15, wherein R¹¹ is selected from among F, Cl, OR¹⁴ and SR¹⁴.
 17. Acompound according to claim 16, wherein R¹¹ is OR¹⁴.
 18. A compoundaccording to claim 1, wherein R¹² is selected from among hydrogen, C₁–C₆alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl,alkynyl, heteroaryl and aryl groups are optionally substituted.
 19. Acompound according to claim 18, wherein R¹² is selected from amonghydrogen, C₁–C₄ alkyl, C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl, whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted.20. A compound according to claim 1, wherein R¹³ is selected from amonghydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, C₂–C₆alkenyl, C₂–C₆ alkynyl, heteroaryl and aryl, wherein the alkyl,haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups areoptionally substituted.
 21. A compound according to claim 20, whereinR¹³ is selected from among hydrogen, C₁–C₄ alkyl, C₁–C₄ haloalkyl andC₁–C₄ heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groupsare optionally substituted.
 22. A compound according to claim 1,wherein: R³ and R⁴ each independently is selected from among hydrogen,C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl,haloalkyl and heteroalkyl groups are optionally substituted; or R³ andR⁵ taken together form a bond; or R⁴ and R⁶ taken together form a fourto six membered saturated or unsaturated carbocyclic ring, wherein thecarbocyclic ring are optionally substituted.
 23. A compound according toclaim 22, wherein R³ and R⁴ each independently is selected from amonghydrogen, C₁–C₄ alkyl, C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl, whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted.24. A compound according to claim 1, wherein: R⁵ and R⁷ eachindependently is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; or R⁵ and R⁷ takentogether form a bond.
 25. A compound according to claim 24, wherein R⁵and R⁷ each independently is selected from among hydrogen, C₁–C₄ alkyl,C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 26. A compound accordingto claim 1, wherein: R⁶ and R⁸ each independently is selected from arehydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, heteroaryland aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and arylgroups are optionally substituted; or R⁶ and R⁸ taken together form athree to eight membered saturated or unsaturated carbocyclic ring,wherein the carbocyclic ring is optionally substituted.
 27. A compoundaccording to claim 26, wherein: R⁶ and R⁸ each independently is selectedfrom among hydrogen, C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₁–C₄ heteroalkyl,heteroaryl and aryl, wherein alkyl, haloalkyl, heteroaryl and aryl areoptionally substituted; or R⁶ and R⁸ taken together form a four to sixmembered saturated or unsaturated carbocyclic ring, wherein thecarbocyclic ring is optionally substituted.
 28. A compound according toclaim 1, wherein: R¹ is selected from among hydrogen, F, Cl, Br, I,substituted C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, whereinthe haloalkyl and heteroalkyl groups are optionally substituted; R² isselected from among hydrogen, F, Cl, Br, CF₃, CF₂Cl, CF₂H, CFH₂,substituted C₁–C₆ alkyl; C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, whereinhaloalkyl and heteroalkyl groups are optionally substituted; and R³ andR⁴ each independently is selected from among hydrogen, C₁–C₆ alkyl,C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 29. A compound accordingto claim 28, wherein: R⁵ through R⁸ each independently is selected fromamong hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted; or R⁶ and R⁸ taken together form a four to six memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringare optionally substituted.
 30. A compound according to claim 29,wherein: R⁹ and R¹⁰ each independently is selected from among hydrogen,F, Cl, Br, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted;R¹² is selected from among hydrogen, C₁–C₆ alkyl C₁–C₆ haloalkyl andC₁–C₆ heteroalkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, heteroaryl and aryl,wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryland aryl groups are optionally substituted; and R¹⁴ is selected fromamong hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl,C(O)R¹⁵, CO₂R¹⁵ and C(O)NR¹⁵R¹⁶, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 31. A compound accordingto claim 30, wherein Y is O or S.
 32. A compound according to claim 1,wherein said compound is selected from among:6-Methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Isopropyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Allyl-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-(4-Methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;4-Trifluoromethyl-5,6,7,8-tetrahydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;4-Trifluoromethyl-5,6,7,8,9,10-hexahydrocyeloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4e,5,6,7,7a(cis),8-Hexahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-4e,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-5,6-Dihydro-5,6-cis-dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-furanylmethyl)-4trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(3-thiophenemethyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2-methylpropyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoro-ethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2-dimethoxyethyl)-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,8,9,9a(cis),10-Octahydro-10-(2,2,2-trifluoroethyl)-4-trifluoromethylcycloheptano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-nitrophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-dimethylaminophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(3-trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-phenyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-(4-methoxyphenyl)-6-methyl-7-(2,2-dimethoxyethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-isopropyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-(2-ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)one;5,6,7,8-Tetrahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano[g]-pyrrolo[3,2-f]-quinolin-2(1H)-one;8-Trifluoroethyl-4-trifluoromethyl-6,8-dihydrocyclopentano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;9-Trifluoroethyl-4-trifluoromethyl-9H-benzo[g]pyrrolo[3,2-f]quinolin-2(1H)-one;5-(3-Trifluoromethylphenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-(4-Fluorophenyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;5-(2-Ethoxycarbonylethyl)-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;5-Methyl-6-(1-hydroxyethyl)-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;5-Methyl-6-acetyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Formyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Acetyloxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;2-Acetyloxy-5-hydroxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinoline;6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Ethoxymethyl-6-ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;(+)-6-(1-Methoxyethyl)-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;7-Allyl-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;6-Ethyl-7-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;7-(3-Trifluoromethylphenyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;7-(2-Hydroxyethyl)-6-methyl-4-trifluoromethyl-5H-pyrrolo[2,3-f]quinolin-2(1H)-one;(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(−)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-7-ethyl-6-hydroxymethyl-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;5-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethylpyrrolo[3,2-f]quinolin-2(1H)-one;6-Formyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;and5,6-Dimethyl-7-(2,2-difluorovinyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one.33. A compound according to claim 1, wherein said compound is selectedfrom the group consisting of:(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-ethyl-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-5,6-Dihydro-5,6-cis-dimethyl-7-4-trifluoromethyl-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-propyl-4-trifluoromethylcyclopentano-[g]pyrrolo-[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-chlorodifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,7a(cis),8-Hexahydro-8-cyclopropylmethyl-4-trifluoromethyl-cyclopentano[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-4c,5,6,7,8,8a(cis)-Hexahydro-9-(2,2,2-trifluoroethyl)-4-trifluoromethyl-9H-cyclohexano[g]pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-6-ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-butyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-Dihydro-5-ethyl-6-propyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(±)-5,6-cis-Dihydro-5-methyl-6-ethyl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[3,2-f]-quinolin-2(1H)-one;5,6-Dimethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;6-Methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;6-Ethyl-5-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5-Ethyl-6-methyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;5,6,7,8-Tetrahydro-8-trifluoroethyl-4-trifluoromethylcyclopentano[g]pyrrolo[3,2-f]-quinolin-2(1H)-one;6-Ethyl-7-(2,2,2-trifluoroethyl)-4-trifluoromethyl-7H-pyrrolo[3,2-f]quinolin-2(1H)-one;(+)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]-pyrrolo[3,2-f]quinolin-2(1H)-one;and(−)-4c,5,6,7,7a(cis),8-Hexahydro-8-(2,2,2-trifluoroethyl)-4-trifluoromethylcyclopentano-[g]pyrrolo[3,2-f]quinolin-2(1H)-one.34. A pharmaceutical composition, comprising: a pharmaceuticallyacceptable carrier; and a compound of formula:

 wherein: R¹ is selected from among hydrogen, F, Cl, Br, I, NO₂, OR¹²,SR¹², SOR¹², SO₂R¹², NR¹²R¹³, C₁–C₈ alkyl, C₁–C₈ haloalkyl and C₁–C₈heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R² is selected from among F, Cl, Br, I, CF₃,CHF₂, CH₂F, CF₂Cl, CN, CF₂OR¹², CH₂OR¹², OR¹², SR¹², SOR¹²,SO₂R^(12, NR) ¹²R¹³, substituted C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈heteroalkyl, C₂–C₈ alkenyl and C₂–C₈ alkynyl, wherein the haloalkyl,heteroalkyl, alkenyl and alkynyl groups are optionally substituted; R³is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁴ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; R⁵ isselected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloroalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁶ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; R⁷ isselected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloroalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted; R⁸ is selected from among hydrogen, F, Cl, Br,I, OR¹², NR¹²R¹³, SR¹², SOR¹², SO₂R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl,C₁–C₈ heteroalkyl, C₂–C₈ alkynyl, C₂–C₈ alkenyl, aryl, heteroaryl andarylalkyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, alkenyl,aryl, heteroaryl and arylalkyl groups are optionally substituted; or R³and R₅ taken together form a bond; or R₅ and R⁷ taken together form abond; or R⁴ and R⁶ taken together form a three- to eight-memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringis optionally substituted; or R⁶ and R⁸ taken together form a three- toeight-membered saturated or unsaturated carbocyclic ring, wherein thecarbocyclic ring is optionally substituted; R⁹ and R¹⁰ eachindependently is selected from among hydrogen, F, Cl, Br, I, CN, OR¹²,NR¹²R¹³, C_(m)(R¹²)_(2m)OR¹³, SR¹², SOR¹², SO₂R¹², NR¹²C(O)R¹³, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl and arylalkyl, wherein thealkyl, haloalkyl, heteroalkyl and arylalkyl groups are optionallysubstituted; R¹¹ is selected from among hydrogen, F, Br, Cl, I, CN,OR¹⁴, NR¹⁴R¹³ and SR¹⁴; R¹² and R¹³ each independently is selected fromamong hydrogen, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈alkenyl, C₂–C₈ alkynyl, heteroaryl and aryl, wherein the alkyl,haloalkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl and aryl groups areoptionally substituted; R¹⁴ is selected from among hydrogen, C₁–C₈alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, aryl, heteroaryl, C(O)R¹⁵,CO2R¹⁵ and C(O)NR¹⁵R¹⁶, wherein the alkyl, haloalkyl, heteroalkyl, aryland heteroaryl groups are optionally substituted; R¹⁵ and R¹⁶ eachindependently is selected from among hydrogen, C₁–C₈ alkyl, C₁–C₈haloalkyl, C₁–C₈ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; W is O or S; X is N{R¹⁴};Y is selected from among O, S, N{R¹²} and N{OR¹²}; Z is N{R¹²}; n is 0;and m is 0 or 1; or a pharmaceutically acceptable salts thereof.
 35. Apharmaceutical composition according to claim 34, wherein the carrier issuitable for enteral, parenteral, suppository, or topicaladministration.
 36. A pharmaceutical composition according to claim 34,wherein R¹ is selected from among hydrogen, F, Cl, Br, I, C₁–C₆ alkyl,C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 37. A pharmaceuticalcomposition according to claim 36, wherein R¹ is selected from amonghydrogen, F, Cl, C₁–C₄ alkyl, C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted.
 38. A pharmaceutical composition according to claim 34,wherein R² is selected from among F, Cl, Br, CF₃, CF₂Cl, CF₂H, CFH₂,substituted C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, whereinthe haloalkyl and heteroalkyl groups are optionally substituted.
 39. Apharmaceutical composition according to claim 38, wherein R² is selectedfrom among F, Cl, Br, CF₃, CF₂Cl, CF₂H, CFH₂, substituted C₁–C₄ alkyl,C₁–C₄ haloalkyl and C₁–C₄ heteroalkyl, wherein the haloalkyl andheteroalkyl groups are optionally substituted.
 40. A pharmaceuticalcomposition according to claim 34, wherein R⁹ and R¹⁰ each independentlyis selected from among hydrogen, F, Cl, Br, C₁–C₆ alkyl, C₁–C₆ haloalkyland C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl and heteroalkylgroups are optionally substituted.
 41. A pharmaceutical compositionaccording to claim 40, wherein R⁹ and R¹⁰ each independently is selectedfrom among hydrogen, F and CH₃.
 42. A pharmaceutical compositionaccording to claim 34, wherein R¹¹ is selected from among hydrogen, F,Cl, CN, OR¹⁴, NR¹⁴R¹³ and SR¹⁴.
 43. A pharmaceutical compositionaccording to claim 42, wherein R¹¹ is selected from among hydrogen, F,Cl, OR¹⁴, SR and NR¹⁴R¹³.
 44. A pharmaceutical composition according toclaim 34, wherein Y is O or S.
 45. A pharmaceutical compositionaccording to claim 34, wherein R¹² is selected from among hydrogen,C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, C₂–C₆ alkenyl, C₂–C₆alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.46. A pharmaceutical composition according to claim 34, wherein: R³ andR⁴ each independently is selected from among hydrogen, C₁–C₆ alkyl,C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; or R³ and R⁵ takentogether form a bond; or R⁴ and R⁶ taken together form a four to sixmembered carbocyclic ring, wherein the carbocyclic ring is optionallysubstituted.
 47. A pharmaceutical composition according to claim 34,wherein: R⁵ and R⁷ each independently is selected from among hydrogen,C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl,haloalkyl and heteroalkyl groups are optionally substituted; or R⁵ andR⁷ taken together form a bond.
 48. A pharmaceutical compositionaccording to claim 34, wherein: R⁶ and R⁸ each independently is selectedfrom among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl,heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,heteroaryl and aryl groups are optionally substituted; or R⁶ and R⁸taken together form a three to eight membered saturated or unsaturatedcarbocyclic ring, wherein the carbocyclic ring is optionallysubstituted.
 49. A pharmaceutical composition according to claim 34,wherein: R¹ is selected from among hydrogen, F, Cl, Br, I, C₁–C₆ alkyl,C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; R² is selected from amongF, Cl, Br, CF₃, CF₂Cl, CF₂H, CFH₂, substituted C₁–C₆ alkyl; C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the haloalkyl and heteroalkylgroups are optionally substituted; and R³ and R⁴ each independently isselected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted.
 50. A pharmaceutical composition according toclaim 49, wherein: R⁵ through R⁸ each independently is selected fromamong hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted; or R₆ and R⁸ taken together form a four to six memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringis optionally substituted.
 51. A pharmaceutical composition according toclaim 50, wherein: R⁹ and R¹⁰ each independently is selected from amonghydrogen, F, Cl, Br, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl,wherein the alkyl, haloalkyl and heteroalkyl groups are optionallysubstituted; R¹² is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl,heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl,alkynyl, heteroaryl and aryl groups are optionally substituted; and R¹⁴is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆heteroalkyl, C(O)R¹⁵, CO₂R¹⁵ and C(O)NR¹⁵R¹⁶, wherein the alkyl,haloalkyl and heteroalkyl groups are optionally substituted.
 52. Apharmaceutical composition according to claim 50, wherein Y is O or S.53. A compound of formula:

wherein: R¹ is selected from among hydrogen, F, Cl, Br, I, NO₂,OR¹²SR¹², SOR¹², SO₂R¹², NR¹² R¹², C₁–C₈ alkyl, C₁–C₈ haloalkyl andC₁–C₈ heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groupsare optionally substituted; R² is selected from among hydrogen F, Cl,Br, CF₃, CHF₂, CH₂F, CF₂Cl, CF₂OR¹², CH₂OR, OR¹², SR¹², SOR¹², SO₂R¹²,NR¹²R¹³, substituted C₁–C₆ alkyl C₁–C₆ haloalkyl, and C₁–C₆ heteroalkyl,wherein the haloalkyl, and heteroalkyl groups are optionallysubstituted; R³ is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; R⁴ is selected from amonghydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆ heteroalkyl, whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted;R⁵ is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl andC₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groupsare optionally substituted; R⁶ is selected from among hydrogen, C₁–C₆alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroaryl and aryl, wherein the alkyl,haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionallysubstituted; R⁷ is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; R⁸ is selected from amonghydrogen, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, heteroaryland aryl, wherein the alkyl, haloalkyl, heteroalkyl, heteroaryl and arylgroups are optionally substituted; or R³ and R₅ taken together form abond; or R₅ and R⁷ taken together form a bond; or R⁴ and R⁶ takentogether form a three- to eight-membered saturated or unsaturatedcarbocyclic ring, wherein the carbocyclic ring is optionallysubstituted; or R⁶ and R⁸ taken together form a three- to eight-memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringis optionally substituted; R⁹ and R¹⁰ each independently is selectedfrom among hydrogen, F, Cl, Br, I, CN, OR¹², NR¹²R¹³,C_(m)(R¹²)_(2m)OR¹³, SR¹², SOR¹², SO₂R¹², NR¹²C(O)R¹³, C₁–C₈ alkyl,C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl and arylalkyl, wherein the alkyl,haloalkyl, heteroalkyl and arylalkyl groups are optionally substituted;R¹¹ is selected from among hydrogen, F, Br, Cl, I, CN, OR¹⁴, NR¹⁴R¹³ andSR¹⁴; R¹² and R¹³ each independently is selected from among hydrogen,C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, C₂–C₈ alkenyl, C₂–C₈alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted;R¹⁴ is selected from among hydrogen, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈heteroalkyl, aryl, heteroaryl, C(O)R¹⁵, CO₂R¹⁵ and C(O)NR¹⁵R¹⁶, whereinthe alkyl, haloalkyl, heteroalkyl, aryl and heteroaryl groups areoptionally substituted; R¹⁵ and R¹⁶ each independently is selected fromamong hydrogen, C₁–C₈ alkyl, C₁–C₈ haloalkyl, C₁–C₈ heteroalkyl, whereinthe alkyl, haloalkyl and heteroalkyl groups are optionally substituted;W is O or S; X is N{R¹⁴}; Y is selected from the groups of O, S, N{R¹²}and NO{R¹²}; Z is N{R¹²}; n is 0; and m is 0 or 1; or a pharmaceuticallyacceptable salts thereof.
 54. A compound according to claim 53, whereinR¹ is selected from among hydrogen, F, Cl, Br, I, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted.
 55. A compound accordingto claim 53, wherein R⁹ and R¹⁰ each independently is selected fromamong hydrogen, F, Cl, Br, C₁–C₆ alkyl, C₁–C₆ haloalkyl and C₁–C₆heteroalkyl, wherein the alkyl, haloalkyl and heteroalkyl groups areoptionally substituted.
 56. A compound according to claim 53, whereinR¹¹ is selected from among F, Cl, CN, OR¹⁴, NR¹⁴R¹³ and SR¹⁴.
 57. Acompound according to claim 53, wherein Y is O or S.
 58. A compoundaccording to claim 53, wherein R¹² is selected from among hydrogen,C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, C₂–C₆ alkenyl, C₂–C₆alkynyl, heteroaryl and aryl, wherein the alkyl, haloalkyl, heteroalkyl,alkenyl, alkynyl, heteroaryl and aryl groups are optionally substituted.59. A compound according to claim 53, wherein: R³ and R⁴ eachindependently is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl and C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; or R³ and R⁵ takentogether form a bond; or R⁴ and R⁶ taken together form a four to sixmembered carbocyclic ring, wherein the carbocyclic ring is optionallysubstituted.
 60. A compound according to claim 34, wherein: R⁵ and R⁷each independently is selected from among hydrogen, C₁–C₆ alkyl, C₁–C₆haloalkyl, C₁–C₆ heteroalkyl, wherein the alkyl, haloalkyl andheteroalkyl groups are optionally substituted; or R⁵ and R⁷ takentogether form a bond.
 61. A compound according to claim 34, wherein: R⁶and R⁸ each independently is selected from among hydrogen, C₁–C₆ alkyl,C₁–C₆ haloalkyl, C₁–C₆ heteroalkyl, heteroaryl and aryl, wherein thealkyl, haloalkyl, heteroalkyl, heteroaryl and aryl groups are optionallysubstituted; or R⁶ and R⁸ taken together form a three to eight memberedsaturated or unsaturated carbocyclic ring, wherein the carbocyclic ringis optionally substituted.